CROSS-REFERENCE This application is a continuation of PCT/US2022/028208, filed May 6, 2022, which claims priority to U.S. Provisional Application No. 63/185,315, filed May 6, 2021, and to U.S. Provisional Application No. 63/315,483, filed Mar. 1, 2022, both of which are incorporated herein by reference.
SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on Jun. 16, 2023, is named ARTN-008_CON-T1_SL.xml and is 985,959 bytes in size.
BACKGROUND Nucleic acid-guided nucleases have become important tools for research and genome engineering. The applicability of these tools can be limited by the sequence specificity requirements, expression, or delivery issues.
INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
FIG. 1 shows a diagram of MAD7 comprising one or more nuclear localization signals (NLS). FIG. 1 discloses “His6” as SEQ ID NO: 423.
FIG. 2 shows editing frequency at the DNMT1 locus in and post-transfection cell viability of T-cell leukemic cells following treatment comprising one or more guide nucleic acids complexed with MAD7 comprising one or more NLS.
FIG. 3 shows editing frequency at the DNMT1 locus in T-cell leukemic cells using multiple electroporation programs in combination with the SE electroporation buffer.
FIG. 4 shows editing frequency at the DNMT1 locus in T-cell leukemic cells using multiple electroporation programs in combination with the SF electroporation buffer.
FIG. 5 shows editing frequency at the DNMT1 locus in T-cell leukemic cells using multiple electroporation programs in combination with the SG electroporation buffer.
FIG. 6 shows editing frequency at the DNMT1 locus in T-cell leukemic cells using multiple electroporation programs.
FIG. 7 shows editing frequency by type at eight loci in T-cell leukemic cells using multiple guide nucleic acids complexed with MAD7 comprising one or more NLS.
FIG. 8 shows a comparison of editing efficiency between T-cell leukemic cells treated with MAD7 comprising one or more guide nucleic acids targeting the DNMT1 locus as compared to a control guide nucleic acid binned by editing frequency.
FIG. 9 shows editing frequency by PAM motif in T-cell leukemic cells using multiple guide nucleic acids complexed with MAD7 comprising one or more NLS.
FIG. 10A shows sequence logo plots for multiple guide nucleic acids binned by editing frequency in T-cell leukemic cells using when complexed with MAD7 comprising one or more NLS.
FIG. 10B shows nucleotide and dinucleotide frequency for multiple guide nucleic acids binned by editing frequency in T-cell leukemic cells using when complexed with MAD7 comprising one or more NLS.
FIG. 11 shows trinucleotide AAA or UUU frequency binned by editing frequency in T-cell leukemic cells following treatment with multiple guide nucleic acids complexed with MAD7 comprising one or more NLS.
FIG. 12 shows editing frequency for both INDELs and frameshift mutations at eight loci in T-cell leukemic cells following treatment with multiple guide nucleic acids complexed with MAD7 comprising one or more NLS.
FIG. 13 shows the correlation between INDEL frequency in the gNA validation experiment versus INDEL formation in the gNA screen experiment.
FIG. 14 shows the proportion of frameshift to INDELs at eight loci in T-cell leukemic cells following treatment with multiple guide nucleic acids complexed with MAD7 comprising one or more NLS.
FIG. 15 shows INDEL frequency for gNAs comprising representative spacer sequences complexed with MAD7 comprising one or more NLS in T-cell leukemic cells at predicted off-target sites. FIG. 15 discloses SEQ ID NOS 424-427, 427-429 and 429-454, respectively, in order of appearance.
FIG. 16 shows INDEL frequency for gNAs comprising representative spacer sequences complexed with MAD7 comprising one or more NLS in T-cell leukemic cells at predicted off-target sites. FIG. 16 discloses SEQ ID NOS 455-484, 453-454 and 485-487, respectively, in order of appearance.
FIG. 17 shows INDEL frequency at the AAVS1 locus in T-cell leukemic cells following treatment with a gNA:MAD7 complex.
FIG. 18 shows GFP insertion efficiency at the AAVS1 locus and cell viability following treatment for multiple primer constructs.
FIG. 19 shows GFP insertion efficiency at the AAVS1 locus with increasing concentrations of donor template (e.g., HDRT) and variable homology arm length.
FIG. 20 shows CAR insertion efficiency at the AAVS1 locus and cell viability with increasing concentrations of donor template and variable homology arm length.
FIG. 21 shows CAR insertion efficiency (A) at the AAVS1 locus and cell viability (B) in primary T-cells.
DETAILED DESCRIPTION CRISPR is an abbreviation of Clustered Regularly Interspaced Short Palindromic Repeats. In a palindromic repeat, the sequence of nucleotides is the same in both directions. Each of these palindromic repetitions is followed by short segments of spacer DNA. Small clusters of Cas (CRISPR-associated system) genes are located next to CRISPR sequences. The CRISPR/Cas system is a prokaryotic immune system that can confer resistance to foreign genetic elements such as those present within plasmids and phages providing the prokaryote a form of acquired immunity. RNA harboring a spacer sequence assists Cas (CRISPR-associated) proteins to recognize and cut exogenous DNA. CRISPR sequences are found in approximately 50% of bacterial genomes and nearly 90% of sequenced archaea has selected for efficient and robust metabolic and regulatory networks that prevent unnecessary metabolite biosynthesis and optimally distribute resources to maximize overall cellular fitness. The complexity of these networks with limited approaches to understand their structure and function and the ability to re-program cellular networks to modify these systems for a diverse range of applications has complicated advances in this space. Certain approaches to re-program cellular networks are directed to modifying single genes of complex pathways but as a consequence of modifying single genes, unwanted modifications to the genes or other genes can result, getting in the way of identifying changes necessary to achieve a sought-after endpoint as well as complicating the endpoint sought by the modification.
CRISPR-Cas driven genome editing and engineering has dramatically impacted biology and biotechnology in general. CRISPR-Cas editing systems require a polynucleotide guided nuclease, a guide nucleic acid (gNA) e.g. a guide RNA (gRNA)) that directs the nuclease to cut a specific region of the genome, and, optionally, a donor DNA cassette (also referred to herein as a donor template or editing sequence) that can be used to repair the cut dsDNA and thereby incorporate programmable edits at the site of interest. The earliest demonstrations and applications of CRISPR-Cas editing used Cas9 nucleases and associated gRNA. These systems have been used for gene editing in a broad range of species encompassing bacteria to higher order mammalian systems such as animals and in certain cases, humans. It is well established, however, that important editing parameters such as protospacer adjacent motif (PAM) specificity, editing efficiency, and off-target rates, among others, are species, loci, and nuclease dependent. There is increasing interest in identifying and rapidly characterizing novel nuclease systems that can be exploited to broaden and improve overall editing capabilities.
One version of the CRISPR/Cas system, CRISPR/Cas9, has been modified to provide useful tools for editing targeted genomes. By delivering the Cas9 nuclease complexed with a synthetic guide RNA (gRNA) into a cell, the cell's genome can be cut/edited at a predetermined location, allowing existing genes to be removed and/or new ones added. These systems are useful but have some important limitations regarding efficiency and accuracy of targeted editing, imprecise editing complications, as well as impediments when used for commercially relevant situations such as gene replacement. Therefore, a need exists for improved nucleic acid guided nuclease systems for directed and accurate editing with improved efficiency.
As used herein, the term “modulating” and “manipulating” of genome editing can mean an increase, a decrease, upregulation, downregulation, induction, a change in editing activity, a change in binding, a change cleavage or the like, of one or more of targeted genes or gene clusters of certain embodiments disclosed herein.
In certain embodiments of the present disclosure, there can be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature and understood by those of skill in the art.
In other embodiments, primers used herein for preparation per conventional techniques can include sequencing primers and amplification primers. In some embodiments, plasmids and oligomers used in conventional techniques can include synthesized oligomers and oligomer cassettes.
In some embodiments disclosed herein, nucleic acid-guided nuclease systems and methods of use are provided. A nuclease system can include transcripts and other elements involved in the expression of an engineered nuclease disclosed herein, which can include sequences encoding a novel engineered nucleic acid-guided nuclease protein and a guide sequence (gRNA) or a novel gRNA as disclosed herein. In some embodiments, nucleic acid-guided nuclease systems can include at least one CRISPR-associated nucleic acid guided nuclease construct, the disclosure of which are provided herein. In other embodiments, nucleic acid-guided nuclease systems can include at least one known guide sequence (gRNA) or at least one novel gRNA, such as a single gRNA or a dual gRNA. In some embodiments, an engineered nucleic acid-guided nuclease of the instant invention can be used in systems for editing a gene of interest in humans or other species.
Bacterial and archaeal targetable nuclease systems have emerged as powerful tools for precision genome editing. However, naturally occurring nucleases have some limitations including expression and delivery challenges due to the nucleic acid sequence and protein size. In certain embodiments, novel engineered nucleic acid-guided nuclease constructs disclosed herein can be created for targeting of a targeted gene and/or increased efficiency and/or accuracy of targeted gene editing in a subject.
In accordance with these embodiments, it is known that Cas12a is a single RNA-guided CRISPR/Cas endonuclease capable of genome editing having differing features when compared to Cas9. In certain embodiments, a Cas12a-based system allow fast and reliable introduction of donor DNA into a genome. In addition, Cas12a broadens genome editing. CRISPR/Cas12a genome editing has been evaluated in human cells as well as other organisms including plants. Several features of the CRISPR/Cas12a system are different when compared to CRISPR/Cas9.
It is known that Cas12a nuclease recognizes T-rich protospacer adjacent motif (PAM) sequences (e.g. 5′-TTTN-3′ (AsCas12a, LbCas12a) and 5′-TTN-3′ (FnCas12a); whereas, the comparable sequence for SpCas9 is NGG. The PAM sequence of Cas12a is located at the 5′ end of the target DNA sequence, where it is at the 3′ end for Cas9. In addition, Cas12a is capable of cleaving DNA distal to its PAM around the +18/+23 position of the protospacer. This cleavage creates a staggered DNA overhang (e.g. sticky ends), whereas Cas9 cleaves close to its PAM after the 3′ position of the protospacer at both strands and creates blunt ends. In certain methods, creating altered recognition of nucleases can provide an improvement over Cas9 or Cas12a to improve accuracy. Further, Cas12a is guided by a single crRNA and does not require a tracrRNA, resulting in a shorter gRNA sequence than the sgRNA used by Cas9. Surprisingly, it has been found that the modified Cas12a nucleases provided herein can also function with a dual gRNA.
It is also known that Cas12a displays additional ribonuclease activity that functions in crRNA processing. Cas12a is used as an editing tool for different species (e.g. S. cerevisiae), allowing the use of an alternative PAM sequence compared with the one recognized by CRISPR/Cas9. Novel nucleases disclosed herein can further recognize the same or alternative PAM sequences. These novel nucleases can provide an alternative system for multiplex genome editing as compared with known multiplex approaches and can be used as an improved system in mammalian gene editing.
Well-known Cas12a protein-RNA complexes recognize a T-rich PAM and cleavage leads to a staggered DNA double-stranded break. Cas12a-type nuclease interacts with the pseudoknot structure formed by the 5′-handle of crRNA. A guide RNA segment, composed of a seed region and the 3′ terminus, possesses complementary binding sequences with the target DNA sequences. Cas12a type nucleases characterized to date have been demonstrated to work with a single gRNA and to process gRNA arrays. While Cas12a-type and Cas9 nuclease systems have proven highly impactful, neither system has been demonstrated to function as predictably as is desired to enable the full range of applications envisioned for gene-editing technologies.
In the current state, a range of efforts have attempted to engineer improved CRISPR editing systems having increased efficiency and accuracy, which have included engineering of the PAM specificity, stability, and sequence of the gRNA and-or the nuclease. For example, chemical modifications of CRISPR/Cas9 gRNA expected to increase gRNA stability was found to lead to a 3.8-fold higher indel frequencies in human cells. In addition, other studies included structure-guided mutagenesis of Cas12a and screened to identify variants with an increased range of recognized PAM sequences. These engineered AsCas12a recognized TYCV and TATV PAMs in addition to the established TTTV sequence, with enhanced activities in vitro and in tested human cells.
In certain embodiments, Cas12a-like nucleases and engineered gRNAs disclosed herein are contemplated for use in bacteria, and other prokaryotes. In certain embodiments, engineered designer nucleases are contemplated for use in eukaryotes such as yeast, mammals, e.g., human as well as of use in birds and fish, or cells derived from same.
In some embodiments, off-targeting rates for nuclease constructs disclosed herein can be reduced compared to a control, e.g., a native sequence, for improved editing. Off-targeting rates can be readily tested.
In some embodiments, nuclease constructs disclosed herein can share conserved encoded motifs of known nucleases. In other embodiments, nuclease constructs disclosed herein do not share conserved encoded peptide motifs with known nucleases. In preferred embodiments, provided herein are compositions, methods, and/or kits wherein the CRISPR nuclease comprises a Type V nuclease. In certain embodiments, provided herein are compositions, methods, and/or kits wherein the CRISPR nuclease comprises a Type V-A, V-B, V-C, V-D, or V-E CRISPR nuclease. In certain embodiments, provided herein are compositions, methods, and/or kits wherein the CRISPR nuclease comprises a Type V-A nuclease. Naturally occurring type V-A CRISPR nucleases comprise a RuvC-like nuclease domain but lack an HNH endonuclease domain, and recognize a 5′ T-rich PAM located immediately upstream from the target nucleotide sequence, the orientation determined using the non-target strand (i.e., the strand not hybridized with the spacer sequence) as the coordinate. These CRISPR nucleases cleave a double-stranded DNA to generate a staggered double-stranded break rather than a blunt end. The cleavage site is distant from the PAM site (e.g., separated by at least 10, 11, 12, 13, 14, or 15 nucleotides downstream from the PAM on the non-target strand and/or separated by at least 15, 16, 17, 18, or 19 nucleotides upstream from the sequence complementary to PAM on the target strand).
In certain embodiments, a type V-A CRISPR nuclease comprises Cpf1. Cpf1 proteins are known in the art and are described, e.g., in U.S. Pat. Nos. 9,790,490 and 10,113,179. Cpf1 orthologs can be found in various bacterial and archaeal genomes. For example, in certain embodiments, the Cpf1 protein is derived from Francisella novicida U112 (Fn), Acidaminococcus sp. BV3L6 (As), Lachnospiraceae bacterium ND2006 (Lb), Lachnospiraceae bacterium MA2020 (Lb2), Candidatus Methanoplasma termitum (CMt), Moraxella bovoculi 237 (Mb), Porphyromonas crevioricanis (Pc), Prevotella disiens (Pd), Francisella tularensis 1, Francisella tularensis subsp. novicida, Prevotella albensis, Lachnospiraceae bacterium MC2017 1, Butyrivibrio proteoclasticus, Peregrinibacteria bacterium GW2011_GWA2_33_10, Parcubacteria bacterium GW2011_GWC2_44_17, Smithella sp. SCADC, Eubacterium eligens, Leptospira inadai, Porphyromonas macacae, Prevotella bryantii, Proteocatella sphenisci, Anaerovibrio sp. RM50, Moraxella caprae, Lachnospiraceae bacterium COE1, or Eubacterium coprostanoligenes.
In certain embodiments, a type V-A CRISPR nuclease comprises AsCpf1 or a variant thereof. In certain embodiments, a type V-A CRISPR nucleases comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 3 of International (PCT) Application Publication No. WO 2021/158918. In certain embodiments, a type V-A CRISPR nucleases comprises the amino acid sequence set forth in SEQ ID NO: 3 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease comprises LbCpf1 or a variant thereof. In certain embodiments, a type V-A CRISPR nucleases comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 4 of International (PCT) Application Publication No. WO 2021158918. In certain embodiments, a type V-A Cas protein comprises the amino acid sequence set forth in SEQ ID NO: 4 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease comprises FnCpf1 or a variant thereof. In certain embodiments, a type V-A Cas protein comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 5 of International (PCT) Application Publication No. WO 2021158918. In certain embodiments, a type V-A Cas protein comprises the amino acid sequence set forth in SEQ ID NO: 5 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease comprises Prevotella bryantii Cpf1 (PbCpf1) or a variant thereof. In certain embodiments, a type V-A Cas protein comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 6 of International (PCT) Application Publication No. WO 2021/158918. In certain embodiments, a type V-A Cas protein comprises the amino acid sequence set forth in SEQ ID NO: 6 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease comprises Proteocatella sphenisci Cpf1 (PsCpf1) or a variant thereof. In certain embodiments, a type V-A Cas protein comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 7 of International (PCT) Application Publication No. WO 2021158918. In certain embodiments, a type V-A Cas protein comprises the amino acid sequence set forth in SEQ ID NO: 7 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease comprises Anaerovibrio sp. RM50 Cpf1 (As2Cpf1) or a variant thereof. In certain embodiments, a type V-A Cas protein comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8 of International (PCT) Application Publication No. WO 2021158918. In certain embodiments, a type V-A Cas protein comprises the amino acid sequence set forth in SEQ ID NO: 8 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease comprises Moraxella caprae Cpf1 (McCpf1) or a variant thereof. In certain embodiments, a type V-A Cas protein comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 9 of International (PCT) Application Publication No. WO 2021/158918. In certain embodiments, a type V-A Cas protein comprises the amino acid sequence set forth in SEQ ID NO: 9 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease comprises Lachnospiraceae bacterium COE1 Cpf1 (Lb3Cpf1) or a variant thereof. In certain embodiments, a type V-A Cas protein comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 10 of International (PCT) Application Publication No. WO 2021158918. In certain embodiments, a type V-A Cas protein comprises the amino acid sequence set forth in SEQ ID NO: 10 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease comprises Eubacterium coprostanoligenes Cpf1 (EcCpf1) or a variant thereof. In certain embodiments, a type V-A Cas protein comprises an amino acid sequence at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 11 of International (PCT) Application Publication No. WO 2021158918. In certain embodiments, a type V-A Cas protein comprises the amino acid sequence set forth in SEQ ID NO: 11 of International (PCT) Application Publication No. WO 2021/158918.
In certain embodiments, a type V-A CRISPR nuclease is not Cpf1. In certain embodiments, a type V-A CRISPR nuclease is not AsCpf1.
In certain embodiments, a type V-A CRISPR nuclease comprises a Type V-A nuclease described in U.S. Pat. No. 9,982,279.
In certain embodiments, a Type VA CRISPR nuclease polypeptide used in compositions and methods herein can be represented by a polypeptide that includes a sequence that has at least 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% sequence identity with SEQ ID NO: 1 SEQ ID NO: 1 wherein the Type VA CRISPR nuclease polypeptide further comprises at least one, two, three, four, five or six nuclear localization sequences (NLS), each of which can be at or near the amino end or carboxy end of the CRISPR nuclease polypeptide; and/or one or more purification tags; in addition, a cleavage sequence can be provided to remove portions of a protopeptide. As used herein, the term “at or near” an N-terminus or a C-terminus includes where the nearest amino acid of the NLS to the N- or C-terminus is within 300 amino acids, in some cases within 200 amino acids, from the N- or C-terminus of the polypeptide (e.g., a core polypeptide such as one of the CRISPR nucleases described herein, to which the NLS or NLSs is attached). In certain embodiments, a Type V CRISPR nuclease polypeptide, e.g., Type Va CRISPR polypeptide, comprises two, three, four, or five NLSs, each of which are at or near the N-terminus or the C-terminus of the polypeptide, in preferred embodiments the NLSs are at or near the N-terminus. In certain embodiments, a CRISPR nuclease polypeptide, including one or more NLSs and, in some cases, a purification tag and/or a cleavage site, comprises a sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to any one of SEQ ID NOs: 109-112. In certain embodiments, a Type V, e.g., VA CRISPR nuclease polypeptide comprises at least 1-30, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 2-30, 2-20, 2-15, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 3-30, 3-20, 3-15, 3-10, 3-9, 3-8, 3-7, 3-6, or 3-5, preferably 1-10, more preferably 2-10, even more preferably 3-10 NLSs, each of which is at or near the N-terminus or the C-terminus of the polypeptide, in preferred embodiments at or near the N-terminus. In certain embodiments, at least two, or at least three, of the NLSs have different mechanisms, that is, different mechanisms by which they localize an attached polypeptide to a nucleus. Such mechanisms are well-known in the art; see, e.g., Lu et al. Cell Commun Signal (2021) 19:60 https://doi.org/10.1186/s12964-021-00741-y. Suitable NLS, purification tag, and cleavage site sequences can be as described elsewhere herein, e.g., in sections labeled Nuclear Localization Signals, Purification Tags, and Cleavage Sites.
SEQ ID NO: 1
MNNGTNNFQNFIGISSLQKTLRNALIPTETTQQFIVKNGIIKEDELRGEN
RQILKDIMDDYYRGFISETLSSIDDIDWTSLFEKMEIQLKNGDNKDTLIK
EQTEYRKAIHKKFANDDRFKNMFSAKLISDILPEFVIHNNNYSASEKEEK
TQVIKLFSRFATSFKDYFKNRANCFSADDISSSSCHRIVNDNAEIFFSNA
LVYRRIVKSLSNDDINKISGDMKDSLKEMSLEEIYSYEKYGEFITQEGIS
FYNDICGKVNSFMNLYCQKNKENKNLYKLQKLHKQILCIADTSYEVPYKF
ESDEEVYQSVNGFLDNISSKHIVERLRKIGDNYNGYNLDKIYIVSKFYES
VSQKTYRDWETINTALEIHYNNILPGNGKSKADKVKKAVKNDLQKSITEI
NELVSNYKLCSDDNIKAETYIHEISHILNNFEAQELKYNPEIHLVESELK
ASELKNVLDVIMNAFHWCSVFMTEELVDKDNNFYAELEEIYDEIYPVISL
YNLVRNYVTQKPYSTKKIKLNFGIPTLADGWSKSKEYSNNAIILMRDNLY
YLGIFNAKNKPDKKIIEGNTSENKGDYKKMIYNLLPGPNKMIPKVFLSSK
TGVETYKPSAYILEGYKQNKHIKSSKDFDITFCHDLIDYFKNCIAIHPEW
KNFGFDFSDTSTYEDISGFYREVELQGYKIDWTYISEKDIDLLQEKGQLY
LFQIYNKDFSKKSTGNDNLHTMYLKNLFSEENLKDIVLKLNGEAEIFFRK
SSIKNPIIHKKGSILVNRTYEAEEKDQFGNIQIVRKNIPENIYQELYKYF
NDKSDKELSDEAAKLKNVVGHHEAATNIVKDYRYTYDKYFLHMPITINFK
ANKTGFINDRILQYIAKEKDLHVIGIDRGERNLIYVSVIDTCGNIVEQKS
FNIVNGYDYQIKLKQQEGARQIARKEWKEIGKIKEIKEGYLSLVIHEISK
MVIKYNAIIAMEDLSYGFKKGRFKVERQVYQKFETMLINKLNYLVFKDIS
ITENGGLLKGYQLTYIPDKLKNVGHQCGCIFYVPAAYTSKIDPTTGFVNI
FKFKDLTVDAKREFIKKFDSIRYDSEKNLFCFTFDYNNFITQNTVMSKSS
WSVYTYGVRIKRRFVNGRFSNESDTIDITKDMEKTLEMTDINWRDGHDLR
QDIIDYEIVQHIFEIFRLTVQMRNSLSELEDRDYDRLISPVLNENNIFYD
SAKAGDALPKDADANGAYCIALKGLYEIKQITENWKEDGKFSRDKLKISN
KDWFDFIQNKRYL
Nucleotide sequences coding for SEQ ID NO: 1 can include sequences with less than 99, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, or 40% sequence identity with SEQ ID NO: 22, in preferred embodiments less than 75% sequence identity. In certain embodiments, a nucleotide sequence coding for SEQ ID NO: 1 can also include nucleic acid sequences coding for one or more NLS at the N-terminus and/or C-terminus, as described herein, and/or a tag such as a purification tag at the N-terminus, as described herein. In certain embodiments, provided herein are compositions comprising a first polynucleotide coding for a polypeptide comprising a nucleic acid-guided nuclease comprising a CRISPR Type V nuclease polypeptide, wherein the polynucleotide has less than 75% sequence identity to SEQ ID NO: 22, such as wherein the nuclease polypeptide comprises at least 1, 2, 3, 4, or 5 NLSs, wherein each of the NLSs is at or near the N-terminus or the C-terminus of the nuclease polypeptide. NLSs can be any of those described herein. The first polynucleotide can comprise a sequence coding for a purification tag, such as a purification tag described herein, and/or cleavage site, such as a cleavage site described herein. In certain embodiments the first polynucleotide codes for a polypeptide comprising a sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to any one of SEQ ID NOs: 109-112, such as SEQ ID NO: 109, or SEQ ID NO: 110, or SEQ ID NO: 111, or SEQ ID NO: 112. the first polynucleotide comprises a sequence at least 50, 60, 70, 80, 90, 95, 97, or 99% identical, or 100% identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to SEQ ID NO: 113. In certain embodiment the composition further comprises a second polynucleotide coding for a gNA or portion thereof, wherein the gNA, e.g., gRNA, comprises a spacer sequence that targets a target nucleotide sequence within a polynucleotide, or a polynucleotide coding for the gNA, e.g., gRNA, wherein the gNA, e.g., gRNA is compatible with the Type V CRISPR nuclease. In certain embodiments the first and second polynucleotides are the same. The composition can further comprise a third polynucleotide comprising a donor template. In certain embodiments, provided is a vector comprising one of the polynucleotide compositions of this paragraph. In certain embodiments, provided is a cell comprising one of the polynucleotide compositions of this paragraph, e.g., a human cell, such as an immune cell, for example a T cell, or a stem cell, such as an iPSC. In certain embodiments, provided is a method comprising inserting any one of the polynucleotide compositions of this paragraph into a cell. In certain embodiments inserting the composition comprises electroporation.
SEQ ID NO: 22:
ATGAACAACGGCACAAATAATTTTCAGAACTTCATCGGGATCTCAAGTTTGCAGAAA
ACGCTGCGCAATGCTCTGATCCCCACGGAAACCACGCAACAGTTCATCGTCAAGAA
CGGAATAATTAAAGAAGATGAGTTACGTGGCGAGAACCGCCAGATTCTGAAAGATA
TCATGGATGACTACTACCGCGGATTCATCTCTGAGACTCTGAGTTCTATTGATGACA
TAGATTGGACTAGCCTGTTCGAAAAAATGGAAATTCAGCTGAAAAATGGTGATAAT
AAAGATACCTTAATTAAGGAACAGACAGAGTATCGGAAAGCAATCCATAAAAAATT
TGCGAACGACGATCGGTTTAAGAACATGTTTAGCGCCAAACTGATTAGTGACATATT
ACCTGAATTTGTCATCCACAACAATAATTATTCGGCATCAGAGAAAGAGGAAAAAA
CCCAGGTGATAAAATTGTTTTCGCGCTTTGCGACTAGCTTTAAAGATTACTTCAAGA
ACCGTGCAAATTGCTTTTCAGCGGACGATATTTCATCAAGCAGCTGCCATCGCATCG
TCAACGACAATGCAGAGATATTCTTTTCAAATGCGCTGGTCTACCGCCGGATCGTAA
AATCGCTGAGCAATGACGATATCAACAAAATTTCGGGCGATATGAAAGATTCATTA
AAAGAAATGAGTCTGGAAGAAATATATTCTTACGAGAAGTATGGGGAATTTATTAC
CCAGGAAGGCATTAGCTTCTATAATGATATCTGTGGGAAAGTGAATTCTTTTATGAA
CCTGTATTGTCAGAAAAATAAAGAAAACAAAAATTTATACAAACTTCAGAAACTTC
ACAAACAGATTCTATGCATTGCGGACACTAGCTATGAGGTCCCGTATAAATTTGAAA
GTGACGAGGAAGTGTACCAATCAGTTAACGGCTTCCTTGATAACATTAGCAGCAAA
CATATAGTCGAAAGATTACGCAAAATCGGCGATAACTATAACGGCTACAACCTGGA
TAAAATTTATATCGTGTCCAAATTTTACGAGAGCGTTAGCCAAAAAACCTACCGCGA
CTGGGAAACAATTAATACCGCCCTCGAAATTCATTACAATAATATCTTGCCGGGTAA
CGGTAAAAGTAAAGCCGACAAAGTAAAAAAAGCGGTTAAGAATGATTTACAGAAAT
CCATCACCGAAATAAATGAACTAGTGTCAAACTATAAGCTGTGCAGTGACGACAAC
ATCAAAGCGGAGACTTATATACATGAGATTAGCCATATCTTGAATAACTTTGAAGCA
CAGGAATTGAAATACAATCCGGAAATTCACCTAGTTGAATCCGAGCTCAAAGCGAG
TGAGCTTAAAAACGTGCTGGACGTGATCATGAATGCGTTTCATTGGTGTTCGGTTTTT
ATGACTGAGGAACTTGTTGATAAAGACAACAATTTTTATGCGGAACTGGAGGAGAT
TTACGATGAAATTTATCCAGTAATTAGTCTGTACAACCTGGTTCGTAACTACGTTACC
CAGAAACCGTACAGCACGAAAAAGATTAAATTGAACTTTGGAATACCGACGTTAGC
AGACGGTTGGTCAAAGTCCAAAGAGTATTCTAATAACGCTATCATACTGATGCGCGA
CAATCTGTATTATCTGGGCATCTTTAATGCGAAGAATAAACCGGACAAGAAGATTAT
CGAGGGTAATACGTCAGAAAATAAGGGTGACTACAAAAAGATGATTTATAATTTGC
TCCCGGGTCCCAACAAAATGATCCCGAAAGTTTTCTTGAGCAGCAAGACGGGGGTG
GAAACGTATAAACCGAGCGCCTATATCCTAGAGGGGTATAAACAGAATAAACATAT
CAAGTCTTCAAAAGACTTTGATATCACTTTCTGTCATGATCTGATCGACTACTTCAAA
AACTGTATTGCAATTCATCCCGAGTGGAAAAACTTCGGTTTTGATTTTAGCGACACC
AGTACTTATGAAGACATTTCCGGGTTTTATCGTGAGGTAGAGTTACAAGGTTACAAG
ATTGATTGGACATACATTAGCGAAAAAGACATTGATCTGCTGCAGGAAAAAGGTCA
ACTGTATCTGTTCCAGATATATAACAAAGATTTTTCGAAAAAATCAACCGGGAATGA
CAACCTTCACACCATGTACCTGAAAAATCTTTTCTCAGAAGAAAATCTTAAGGATAT
CGTCCTGAAACTTAACGGCGAAGCGGAAATCTTCTTCAGGAAGAGCAGCATAAAGA
ACCCAATCATTCATAAAAAAGGCTCGATTTTAGTCAACCGTACCTACGAAGCAGAA
GAAAAAGACCAGTTTGGCAACATTCAAATTGTGCGTAAAAATATTCCGGAAAACAT
TTATCAGGAGCTGTACAAATACTTCAACGATAAAAGCGACAAAGAGCTGTCTGATG
AAGCAGCCAAACTGAAGAATGTAGTGGGACACCACGAGGCAGCGACGAATATAGTC
AAGGACTATCGCTACACGTATGATAAATACTTCCTTCATATGCCTATTACGATCAAT
TTCAAAGCCAATAAAACGGGTTTTATTAATGATAGGATCTTACAGTATATCGCTAAA
GAAAAAGACTTACATGTGATCGGCATTGATCGGGGCGAGCGTAACCTGATCTACGT
GTCCGTGATTGATACTTGTGGTAATATAGTTGAACAGAAAAGCTTTAACATTGTAAA
CGGCTACGACTATCAGATAAAACTGAAACAACAGGAGGGCGCTAGACAGATTGCGC
GGAAAGAATGGAAAGAAATTGGTAAAATTAAAGAGATCAAAGAGGGCTACCTGAG
CTTAGTAATCCACGAGATCTCTAAAATGGTAATCAAATACAATGCAATTATAGCGAT
GGAGGATTTGTCTTATGGTTTTAAAAAAGGGCGCTTTAAGGTCGAACGGCAAGTTTA
CCAGAAATTTGAAACCATGCTCATCAATAAACTCAACTATCTGGTATTTAAAGATAT
TTCGATTACCGAGAATGGCGGTCTCCTGAAAGGTTATCAGCTGACATACATTCCTGA
TAAACTTAAAAACGTGGGTCATCAGTGCGGCTGCATTTTTTATGTGCCTGCTGCATA
CACGAGCAAAATTGATCCGACCACCGGCTTTGTGAATATCTTTAAATTTAAAGACCT
GACAGTGGACGCAAAACGTGAATTCATTAAAAAATTTGACTCAATTCGTTATGACAG
TGAAAAAAATCTGTTCTGCTTTACATTTGACTACAATAACTTTATTACGCAAAACAC
GGTCATGAGCAAATCATCGTGGAGTGTGTATACATACGGCGTGCGCATCAAACGTC
GCTTTGTGAACGGCCGCTTCTCAAACGAAAGTGATACCATTGACATAACCAAAGATA
TGGAGAAAACGTTGGAAATGACGGACATTAACTGGCGCGATGGCCACGATCTTCGT
CAAGACATTATAGATTATGAAATTGTTCAGCACATATTCGAAATTTTCCGTTTAACA
GTGCAAATGCGTAACTCCTTGTCTGAACTGGAGGACCGTGATTACGATCGTCTCATT
TCACCTGTACTGAACGAAAATAACATTTTTTATGACAGCGCGAAAGCGGGGGATGC
ACTTCCTAAGGATGCCGATGCAAATGGTGCGTATTGTATTGCATTAAAAGGGTTATA
TGAAATTAAACAAATTACCGAAAATTGGAAAGAAGATGGTAAATTTTCGCGCGATA
AACTCAAAATCAGCAATAAAGATTGGTTCGACTTTATCCAGAATAAGCGCTATCTCT
AA
Exemplary nucleotide sequences coding for SEQ ID NO: 1 can include, e.g., SEQ ID NOs: 23-42:
SEQ ID NO: 23
ATGAACAACGGAACAAATAATTTTCAGAACTTTATTGGGATCAGTTCGCTTCAGAAA
ACGCTTCGTAATGCTCTGATTCCCACAGAAACCACTCAGCAGTTTATCGTAAAGAAT
GGCATTATCAAGGAGGATGAATTACGCGGCGAGAACCGCCAAATCTTAAAAGATAT
CATGGACGACTACTACCGCGGTTTCATTAGCGAAACTCTTAGTTCAATTGACGACAT
TGACTGGACGTCCTTGTTCGAAAAGATGGAGATTCAATTAAAGAACGGTGATAACA
AGGATACGTTGATTAAAGAACAGACGGAGTACCGTAAGGCTATCCACAAAAAATTT
GCAAACGACGACCGCTTTAAAAATATGTTTAGCGCAAAATTAATCTCCGACATCCTG
CCTGAATTCGTCATCCATAACAATAACTATAGCGCCTCGGAAAAAGAAGAAAAAAC
GCAGGTTATTAAACTTTTCTCGCGCTTTGCAACAAGCTTTAAGGATTACTTCAAAAA
TCGCGCCAATTGTTTTTCAGCCGACGACATTAGCTCCAGTTCCTGCCACCGTATTGTG
AATGACAACGCTGAGATTTTTTTTTCCAATGCGCTGGTTTATCGTCGTATTGTTAAGA
GCCTTAGTAACGACGACATTAATAAAATTAGCGGTGATATGAAGGATAGCTTGAAA
GAAATGAGTCTGGAAGAGATCTATAGTTACGAGAAGTACGGCGAATTTATTACCCA
GGAGGGCATTTCATTTTACAATGATATCTGTGGAAAAGTCAACTCCTTTATGAACTT
GTATTGCCAAAAGAATAAAGAAAACAAAAACCTGTACAAACTGCAAAAGTTACACA
AGCAGATTTTGTGTATCGCAGACACGTCATACGAAGTACCGTACAAGTTTGAGTCCG
ATGAAGAAGTGTACCAAAGCGTTAATGGCTTTTTGGATAACATTTCGAGCAAACATA
TCGTAGAGCGTTTGCGTAAGATTGGTGATAATTACAACGGTTACAATTTAGACAAAA
TCTATATCGTCTCTAAGTTTTACGAAAGTGTTTCTCAGAAAACTTACCGCGATTGGG
AGACGATCAACACTGCGCTGGAGATTCATTACAATAATATCCTTCCAGGTAACGGTA
AAAGCAAAGCTGATAAGGTGAAAAAGGCGGTTAAAAATGACCTTCAAAAGTCTATC
ACAGAAATCAACGAATTGGTCAGCAATTATAAGCTTTGCAGTGACGATAACATTAA
GGCCGAGACTTACATCCATGAGATCTCTCACATTCTTAATAATTTTGAAGCGCAAGA
GCTGAAATACAATCCTGAAATCCATCTGGTCGAAAGTGAATTAAAAGCCTCCGAATT
AAAAAATGTCTTGGACGTGATCATGAATGCGTTCCATTGGTGCTCAGTTTTTATGAC
GGAAGAGTTGGTGGACAAAGACAACAATTTTTACGCCGAGCTTGAGGAAATTTACG
ACGAAATTTACCCCGTTATTTCGTTATACAACCTTGTGCGTAATTACGTTACACAAA
AGCCCTATTCGACAAAGAAAATCAAGTTAAATTTCGGGATTCCCACATTAGCTGATG
GATGGTCCAAATCCAAAGAATACTCGAATAACGCTATCATCCTTATGCGTGATAATT
TGTACTACTTAGGCATCTTCAATGCGAAGAACAAACCTGACAAGAAAATTATCGAA
GGAAACACTTCGGAGAACAAAGGTGATTATAAAAAGATGATCTACAACTTGCTTCC
CGGGCCAAACAAAATGATTCCCAAGGTATTTTTGAGTTCTAAAACCGGTGTCGAAAC
TTACAAACCAAGTGCTTATATTTTGGAAGGATACAAACAGAACAAACATATCAAGT
CTTCGAAAGACTTCGATATTACGTTCTGCCACGATCTGATCGATTACTTCAAGAACT
GTATTGCTATTCACCCCGAGTGGAAGAACTTTGGATTTGATTTCTCCGACACGTCCA
CTTATGAAGATATCTCTGGCTTCTATCGCGAGGTTGAATTACAAGGGTATAAGATTG
ACTGGACTTATATTTCGGAGAAGGATATCGATCTTTTGCAAGAAAAAGGGCAACTTT
ATTTATTTCAGATCTATAACAAGGACTTTTCAAAAAAGAGCACTGGAAATGACAATC
TGCATACCATGTACCTTAAGAACCTGTTCTCGGAAGAGAACCTGAAGGACATTGTAC
TTAAACTGAATGGAGAGGCAGAGATCTTCTTTCGCAAATCAAGCATTAAGAACCCA
ATTATTCACAAAAAGGGGAGTATCTTAGTAAATCGCACATATGAGGCTGAGGAAAA
AGATCAGTTTGGTAACATTCAGATCGTGCGTAAGAACATTCCTGAAAATATCTATCA
GGAACTTTATAAGTATTTCAACGATAAAAGTGATAAAGAGCTGAGTGACGAAGCGG
CTAAACTTAAGAATGTTGTGGGACACCATGAGGCAGCAACCAATATTGTGAAGGAT
TATCGCTATACGTACGACAAATACTTTTTACACATGCCCATCACTATTAATTTTAAAG
CTAATAAGACTGGCTTCATTAACGATCGCATCCTGCAGTACATTGCTAAGGAAAAGG
ATCTTCACGTTATCGGTATCGATCGCGGGGAGCGTAATCTTATCTACGTCTCTGTCAT
TGACACGTGTGGCAATATTGTGGAGCAAAAGTCCTTCAATATTGTTAACGGCTATGA
CTATCAGATTAAATTGAAACAGCAGGAAGGTGCGCGTCAGATTGCCCGCAAGGAAT
GGAAGGAAATTGGCAAGATCAAAGAAATTAAGGAGGGCTACTTAAGCTTAGTAATT
CACGAAATTAGTAAAATGGTTATCAAATACAACGCCATCATCGCGATGGAGGATCTT
TCGTACGGGTTTAAGAAAGGTCGTTTTAAAGTGGAGCGTCAGGTGTACCAGAAATTT
GAAACTATGCTTATTAACAAACTTAACTACCTGGTTTTCAAGGATATCAGTATTACT
GAAAACGGGGGGCTGTTAAAAGGGTATCAATTAACTTACATTCCAGACAAATTAAA
GAACGTTGGACATCAGTGTGGCTGCATTTTTTATGTACCAGCTGCATACACTTCAAA
GATCGATCCTACGACTGGGTTCGTGAACATTTTTAAGTTTAAAGACTTGACGGTAGA
TGCCAAGCGCGAATTCATCAAGAAATTCGACAGCATTCGCTACGACTCTGAGAAAA
ATCTTTTCTGTTTCACATTCGATTATAACAATTTCATTACGCAGAACACAGTAATGTC
CAAGTCTTCTTGGAGTGTTTATACATATGGTGTCCGCATTAAGCGCCGTTTCGTCAAC
GGCCGCTTCAGTAATGAGAGCGATACTATTGACATCACAAAAGACATGGAAAAAAC
ACTGGAAATGACCGACATCAATTGGCGTGACGGCCATGACTTACGTCAGGATATCAT
TGATTATGAGATCGTTCAACACATCTTCGAAATCTTTCGCTTGACTGTTCAAATGCGC
AATTCCTTGTCGGAATTGGAGGACCGTGATTATGACCGCTTAATTTCCCCCGTCTTAA
ATGAAAACAATATTTTTTATGACTCTGCAAAAGCTGGAGATGCTCTGCCGAAAGACG
CCGATGCAAATGGGGCATATTGCATTGCTTTAAAGGGGCTTTACGAGATCAAGCAA
ATCACCGAAAACTGGAAAGAGGATGGAAAGTTTTCGCGTGATAAACTGAAGATCTC
TAACAAAGACTGGTTCGACTTTATCCAGAACAAGCGTTATTT
SEQ ID NO: 24
ATGAACAACGGCACCAATAACTTCCAAAACTTCATCGGGATCTCTAGCCTTCAGAAG
ACGCTTCGCAATGCTCTTATCCCAACTGAGACCACTCAACAATTTATTGTGAAGAAT
GGAATTATTAAAGAGGACGAACTGCGTGGCGAGAATCGTCAGATCTTAAAGGACAT
TATGGATGATTATTACCGTGGATTCATCTCCGAAACATTATCGTCGATCGATGATAT
CGATTGGACTTCTCTGTTCGAGAAAATGGAAATTCAATTGAAAAACGGAGATAATA
AAGATACGCTTATCAAAGAACAGACGGAATATCGTAAAGCGATTCATAAGAAATTC
GCAAATGACGATCGTTTCAAAAATATGTTCAGTGCCAAGCTTATTTCGGACATTTTA
CCTGAATTTGTAATTCATAATAATAACTACTCAGCAAGTGAGAAGGAGGAGAAAAC
CCAAGTTATTAAACTGTTCTCTCGTTTCGCAACGTCCTTTAAAGATTACTTTAAAAAC
CGCGCGAATTGCTTTAGCGCTGACGACATTTCCAGCTCATCCTGTCATCGCATCGTA
AACGACAATGCGGAAATCTTCTTCAGCAACGCCCTGGTTTACCGCCGCATCGTCAAA
AGCTTATCGAATGACGACATCAATAAGATCTCAGGAGATATGAAGGACTCGCTTAA
GGAGATGTCTCTGGAGGAAATTTATAGTTACGAAAAGTATGGAGAGTTCATTACCCA
GGAGGGAATCTCGTTCTACAATGACATTTGCGGGAAGGTGAACTCCTTCATGAACTT
ATACTGCCAGAAAAACAAAGAGAACAAAAATCTGTATAAATTGCAGAAATTACATA
AACAGATTCTTTGTATTGCTGACACTTCCTACGAAGTACCCTATAAATTCGAGTCAG
ATGAAGAAGTATACCAGTCCGTGAACGGATTTCTGGACAATATCTCCTCAAAACACA
TCGTGGAACGCTTACGTAAAATTGGCGATAATTATAATGGTTACAATCTTGACAAAA
TTTATATCGTATCTAAATTTTACGAGAGTGTGAGCCAAAAGACCTACCGCGACTGGG
AGACCATCAACACAGCTTTAGAAATTCACTATAATAATATCTTACCCGGCAATGGTA
AGAGCAAGGCTGACAAGGTAAAAAAGGCCGTCAAGAATGATTTGCAGAAATCTATT
ACAGAAATTAATGAGTTAGTCTCCAACTATAAGCTTTGTTCCGACGATAACATCAAA
GCTGAGACATATATTCATGAGATTAGTCACATTCTTAACAACTTCGAGGCCCAGGAA
CTTAAGTACAATCCTGAAATTCATCTTGTCGAGTCTGAGCTGAAAGCTAGTGAATTG
AAAAATGTTTTAGACGTTATTATGAACGCATTCCACTGGTGCTCTGTGTTTATGACA
GAAGAACTGGTCGACAAGGACAATAACTTCTATGCCGAACTTGAGGAAATCTACGA
TGAAATTTACCCTGTAATCTCCTTGTATAATCTTGTACGTAATTACGTCACTCAAAAA
CCTTACAGCACGAAAAAAATTAAATTGAACTTCGGGATTCCTACACTTGCCGACGGG
TGGTCTAAATCCAAGGAATATAGCAACAATGCCATTATTTTAATGCGCGACAATCTT
TACTATTTAGGAATTTTTAACGCTAAGAACAAGCCCGATAAAAAGATTATTGAAGGA
AACACGTCTGAAAATAAGGGCGACTACAAAAAGATGATTTATAACCTTTTGCCCGGT
CCAAACAAAATGATCCCAAAGGTATTCCTGTCATCCAAAACAGGGGTTGAGACATA
TAAGCCCAGCGCATATATTCTGGAAGGATACAAACAGAATAAACATATCAAAAGCA
GCAAAGATTTTGACATTACTTTTTGCCACGATTTAATCGACTACTTCAAAAACTGTAT
CGCTATCCACCCTGAATGGAAGAATTTCGGATTTGATTTCTCAGATACAAGTACGTA
TGAGGATATCAGCGGTTTCTATCGCGAAGTTGAACTTCAAGGGTATAAAATTGACTG
GACCTACATTAGTGAGAAGGACATCGACCTGTTACAGGAAAAAGGCCAATTGTACT
TGTTTCAGATCTACAATAAGGATTTCTCAAAAAAATCGACCGGCAATGATAACTTGC
ACACCATGTACCTGAAGAACCTTTTTTCGGAGGAAAACCTTAAAGACATTGTCCTGA
AGTTGAATGGAGAAGCGGAGATTTTCTTTCGTAAGTCTTCCATTAAAAATCCAATTA
TTCATAAGAAGGGCAGCATCCTTGTGAACCGTACGTACGAGGCGGAAGAGAAGGAC
CAATTCGGTAACATTCAAATCGTCCGCAAGAACATCCCTGAAAATATTTATCAGGAG
CTTTACAAGTATTTCAATGATAAGTCCGACAAGGAATTATCAGATGAGGCTGCGAAG
TTGAAAAATGTTGTTGGTCATCACGAGGCGGCGACGAATATTGTAAAGGATTATCGC
TACACTTATGACAAGTACTTTCTGCACATGCCGATCACCATTAATTTCAAGGCGAAC
AAAACAGGATTTATTAATGACCGCATCTTACAATACATTGCCAAAGAAAAGGACTT
ACACGTTATTGGCATTGATCGTGGAGAACGCAACTTAATCTACGTAAGCGTTATTGA
CACTTGCGGGAATATCGTAGAACAAAAGAGCTTCAACATCGTGAATGGTTACGATT
ACCAGATCAAGCTTAAGCAGCAGGAGGGAGCGCGCCAGATCGCGCGCAAGGAATG
GAAGGAGATTGGTAAGATCAAGGAAATCAAGGAAGGTTATCTGTCCTTGGTAATCC
ACGAAATTTCGAAAATGGTTATCAAATACAATGCTATTATTGCAATGGAGGACTTGT
CCTACGGCTTTAAAAAAGGACGCTTTAAGGTGGAGCGCCAGGTTTATCAAAAGTTTG
AAACAATGCTGATTAACAAGCTGAACTATTTGGTCTTTAAAGATATCTCCATCACCG
AAAATGGTGGGCTTTTGAAAGGCTATCAACTTACATATATCCCTGATAAGCTTAAGA
ATGTGGGTCATCAGTGCGGGTGCATTTTTTATGTTCCTGCAGCCTACACGTCCAAAA
TCGATCCTACAACTGGATTTGTTAATATCTTCAAATTTAAGGATCTTACCGTCGACGC
GAAGCGCGAATTTATCAAGAAATTCGATAGTATTCGTTATGATTCCGAAAAAAACCT
TTTCTGTTTCACCTTTGATTATAATAACTTTATCACGCAAAATACTGTCATGAGCAAA
TCGAGTTGGTCTGTGTACACTTACGGAGTACGCATCAAGCGTCGTTTTGTTAATGGG
CGCTTCAGTAACGAGTCAGACACGATTGATATCACAAAAGATATGGAGAAAACGCT
GGAGATGACAGACATCAATTGGCGCGATGGTCATGACTTACGTCAAGACATTATCG
ATTATGAAATTGTCCAGCATATCTTTGAGATCTTTCGTTTGACTGTTCAGATGCGCAA
CAGCCTGTCAGAATTGGAGGATCGTGACTATGATCGCCTTATTTCTCCCGTCTTAAAT
GAGAACAATATCTTCTACGACTCAGCCAAGGCTGGAGATGCACTGCCAAAAGACGC
CGACGCAAATGGGGCCTACTGTATTGCATTGAAGGGGTTGTACGAGATCAAACAGA
TTACAGAAAATTGGAAGGAGGACGGTAAGTTCTCTCGTGATAAGCTGAAGATTTCTA
ACAAAGACTGGTTCGATTTCATTCAGAACAAACGTTACCTG
SEQ ID NO: 25
ATGAACAACGGTACCAATAACTTTCAGAATTTCATTGGAATCAGCAGCTTACAGAAA
ACCCTGCGCAATGCACTTATCCCCACTGAGACAACCCAGCAGTTCATTGTAAAGAAC
GGGATTATTAAAGAAGATGAGCTTCGCGGGGAGAATCGTCAGATCTTAAAGGATAT
TATGGACGATTACTACCGTGGCTTCATTTCGGAGACGCTGTCGTCGATCGACGACAT
CGACTGGACATCCTTGTTTGAAAAGATGGAAATCCAACTGAAGAATGGCGATAACA
AGGACACGTTAATCAAAGAGCAGACGGAATACCGTAAAGCTATCCACAAAAAGTTC
GCTAATGACGACCGCTTTAAGAACATGTTCTCAGCAAAACTTATTAGCGATATTTTA
CCTGAATTTGTCATCCACAATAACAATTACTCCGCGAGTGAAAAAGAGGAGAAAAC
CCAGGTGATTAAGCTGTTTTCCCGTTTTGCAACCAGTTTCAAGGACTATTTTAAGAAT
CGTGCTAATTGTTTCTCTGCAGACGACATTTCCTCGTCGTCCTGCCATCGCATTGTTA
ATGATAATGCTGAAATCTTTTTTTCAAACGCACTTGTGTATCGTCGCATTGTCAAAAG
CTTAAGTAATGACGATATCAATAAGATCTCAGGAGACATGAAGGACTCCCTGAAAG
AAATGTCATTGGAAGAAATTTACTCTTATGAAAAGTATGGAGAATTTATTACGCAGG
AGGGTATCAGCTTCTATAACGACATTTGTGGTAAAGTGAACAGCTTTATGAATCTTT
ATTGTCAAAAGAATAAAGAGAACAAAAATCTGTACAAGCTGCAGAAATTGCATAAA
CAAATTCTGTGCATTGCAGATACTTCGTATGAGGTTCCTTACAAATTCGAGTCGGAT
GAGGAGGTGTATCAAAGCGTAAACGGATTTTTGGATAACATTAGTAGTAAGCATATT
GTGGAACGCCTTCGCAAGATTGGTGACAACTATAACGGATACAACTTAGACAAGAT
CTATATTGTCTCGAAGTTTTACGAAAGTGTTTCCCAAAAGACTTATCGCGACTGGGA
GACAATCAACACTGCGCTGGAAATTCACTATAACAATATCTTGCCGGGGAACGGAA
AAAGTAAGGCAGATAAGGTGAAGAAAGCAGTCAAAAATGATCTGCAAAAAAGCAT
TACTGAAATTAACGAACTTGTGTCAAATTACAAATTGTGTTCGGATGACAATATTAA
AGCGGAAACGTATATCCACGAGATCTCGCACATTCTTAATAATTTCGAGGCGCAGGA
ATTAAAGTATAATCCTGAGATCCATTTGGTGGAATCAGAACTTAAAGCTAGTGAACT
GAAAAATGTCCTGGACGTTATTATGAATGCATTTCACTGGTGTTCTGTCTTTATGACA
GAAGAACTTGTCGACAAAGACAACAACTTTTATGCGGAATTAGAAGAGATTTACGA
CGAAATTTATCCCGTTATTTCGTTATATAATTTAGTTCGTAATTACGTGACTCAGAAA
CCCTACAGCACAAAAAAGATTAAATTAAACTTTGGGATTCCGACTCTTGCTGATGGA
TGGAGCAAGTCCAAGGAGTACTCTAATAACGCCATTATCTTGATGCGTGACAACCTG
TACTACCTGGGCATTTTTAACGCTAAAAACAAACCCGACAAAAAGATCATTGAAGG
GAACACCTCGGAAAATAAGGGGGACTATAAAAAAATGATCTACAATCTGTTGCCAG
GCCCAAATAAGATGATCCCAAAGGTTTTTTTATCTTCCAAAACTGGCGTAGAAACTT
ACAAGCCGAGCGCATACATCCTTGAAGGATATAAACAAAACAAACATATCAAAAGT
TCAAAGGACTTCGATATTACGTTCTGCCATGATTTAATCGATTATTTCAAGAATTGCA
TCGCGATTCACCCAGAGTGGAAAAACTTTGGGTTTGATTTTTCAGACACCAGCACTT
ACGAGGATATTAGTGGATTCTATCGTGAGGTTGAACTGCAGGGCTATAAAATTGACT
GGACCTATATTTCTGAAAAAGATATTGATCTGCTTCAGGAGAAAGGCCAATTGTACT
TATTTCAAATCTATAACAAGGATTTCTCCAAGAAGTCCACGGGTAATGACAACTTAC
ACACAATGTATCTGAAGAATCTGTTTAGTGAGGAGAACTTGAAGGACATTGTGCTGA
AGCTTAATGGCGAGGCCGAAATCTTTTTTCGTAAGTCCTCCATTAAAAACCCTATTA
TCCATAAGAAAGGGAGTATTCTTGTCAACCGCACGTATGAGGCCGAAGAAAAGGAC
CAATTCGGAAACATCCAAATTGTCCGTAAAAATATTCCTGAGAACATTTACCAGGAG
CTTTACAAGTATTTCAACGACAAGAGTGATAAAGAACTTTCAGATGAGGCGGCGAA
ACTGAAGAATGTAGTGGGGCACCACGAAGCTGCCACGAATATTGTAAAGGATTACC
GTTACACCTACGACAAGTACTTTTTGCATATGCCCATCACAATTAATTTTAAGGCCA
ATAAAACTGGTTTTATCAACGATCGTATCTTACAGTACATTGCTAAGGAAAAAGATC
TGCACGTTATCGGTATCGATCGCGGGGAACGCAATCTGATTTATGTTAGTGTGATTG
ACACGTGCGGAAATATTGTTGAGCAGAAGAGCTTTAATATCGTAAATGGATATGACT
ATCAAATTAAACTGAAGCAACAGGAAGGGGCCCGCCAGATTGCCCGCAAGGAGTGG
AAAGAAATTGGAAAGATCAAGGAGATTAAAGAAGGGTACCTTTCCCTTGTTATCCA
CGAAATCTCGAAAATGGTGATCAAGTACAATGCCATTATTGCTATGGAGGATCTGTC
ATATGGGTTTAAGAAAGGCCGCTTTAAGGTGGAACGTCAGGTTTACCAGAAGTTTGA
GACCATGCTTATCAATAAGCTGAATTATCTTGTCTTCAAAGACATCTCAATCACAGA
GAACGGCGGGCTGTTAAAAGGATATCAGCTGACCTATATCCCCGACAAACTGAAAA
ATGTCGGGCACCAATGCGGCTGTATTTTCTACGTGCCCGCTGCATACACATCTAAAA
TTGACCCAACGACTGGATTCGTAAATATTTTTAAGTTTAAGGATCTTACGGTAGATG
CAAAGCGCGAATTTATCAAGAAATTTGATAGTATCCGTTACGACAGCGAGAAAAAC
TTATTTTGTTTTACGTTCGATTATAACAACTTCATCACGCAAAATACCGTCATGTCAA
AATCTTCCTGGTCAGTCTATACGTATGGCGTCCGTATCAAGCGCCGCTTCGTCAACG
GGCGTTTTTCAAACGAGTCAGATACCATCGATATCACCAAAGATATGGAAAAAACA
TTGGAGATGACGGACATCAATTGGCGCGATGGTCATGACTTACGCCAGGACATTATT
GACTACGAAATCGTACAACATATTTTTGAGATTTTCCGTCTGACCGTGCAAATGCGC
AACTCATTATCCGAACTTGAGGATCGTGATTACGACCGCTTGATCAGTCCTGTTCTG
AACGAGAATAATATTTTTTACGACAGTGCCAAGGCGGGAGACGCACTGCCCAAGGA
CGCTGACGCTAACGGAGCTTATTGTATTGCGTTGAAGGGACTTTACGAAATCAAGCA
AATCACTGAAAACTGGAAGGAGGATGGTAAATTCTCACGCGACAAGTTGAAAATTT
CGAACAAGGACTGGTTCGATTTCATCCAAAACAAGCGTTATTTA
SEQ ID NO: 26
ATGAACAACGGGACTAATAACTTCCAGAACTTCATCGGTATTTCATCATTACAAAAA
ACGCTTCGTAACGCCTTGATCCCAACAGAAACGACCCAACAATTTATTGTAAAAAAC
GGCATCATCAAAGAAGACGAACTGCGTGGCGAAAATCGCCAAATTTTGAAGGACAT
TATGGATGACTATTATCGTGGGTTTATCTCGGAGACATTATCCTCCATCGACGACATT
GATTGGACGAGTCTTTTTGAGAAAATGGAGATCCAGCTTAAAAATGGTGATAACAA
GGATACATTGATCAAGGAGCAAACCGAGTACCGCAAGGCCATCCATAAGAAGTTCG
CAAATGACGACCGCTTCAAAAATATGTTTAGTGCCAAATTGATCTCGGATATCCTTC
CTGAGTTCGTAATTCACAACAATAATTATAGCGCATCCGAAAAGGAGGAAAAGACT
CAAGTCATTAAGCTTTTCAGTCGCTTTGCTACCTCGTTTAAGGACTATTTCAAGAACC
GCGCGAACTGCTTCTCAGCGGATGACATTTCTTCCTCGTCGTGTCACCGCATCGTGA
ATGATAATGCGGAGATCTTCTTTAGTAATGCCTTGGTATACCGCCGCATTGTTAAAT
CCCTGTCTAACGACGATATCAATAAGATCTCAGGAGATATGAAGGATAGCCTTAAA
GAAATGTCTCTGGAAGAAATTTACTCCTATGAAAAGTACGGTGAGTTTATCACCCAA
GAGGGGATTAGCTTTTATAACGATATCTGCGGGAAGGTGAATTCGTTTATGAACCTT
TATTGTCAAAAGAATAAGGAGAATAAGAACTTATATAAGCTTCAGAAACTGCATAA
ACAAATCTTATGCATTGCCGATACTAGCTATGAAGTTCCGTATAAATTCGAGAGCGA
TGAAGAAGTTTATCAGAGCGTCAATGGGTTCTTGGATAACATTTCATCAAAACACAT
CGTGGAACGTCTGCGTAAGATTGGGGATAACTACAACGGATATAATCTTGACAAAA
TTTATATTGTATCTAAATTCTATGAGTCGGTGAGTCAAAAGACCTACCGTGATTGGG
AAACAATCAATACCGCGTTAGAAATCCACTATAACAACATTCTGCCAGGGAATGGT
AAAAGTAAAGCGGACAAAGTCAAGAAGGCTGTGAAGAACGATCTGCAAAAGAGTA
TTACAGAGATTAACGAATTAGTCTCCAATTATAAGTTATGCTCGGACGATAACATTA
AGGCGGAGACGTATATTCATGAGATTTCGCATATTCTTAACAACTTCGAGGCACAAG
AGCTTAAGTATAACCCAGAGATTCACCTTGTCGAATCGGAGCTGAAGGCATCGGAA
TTAAAAAATGTCTTAGATGTAATCATGAACGCGTTCCATTGGTGCAGTGTTTTCATG
ACTGAGGAGTTAGTTGACAAGGACAATAACTTCTACGCAGAATTAGAAGAGATCTA
TGATGAGATTTATCCAGTGATTTCGCTGTATAATCTGGTACGTAATTACGTCACTCAA
AAGCCCTACTCAACAAAAAAAATTAAGCTGAACTTCGGAATTCCGACTCTGGCCGA
CGGGTGGTCCAAGTCAAAGGAGTATTCTAATAATGCTATCATCCTGATGCGCGATAA
CTTATACTATTTGGGAATTTTCAATGCCAAAAATAAACCAGATAAAAAGATTATCGA
AGGTAATACAAGCGAGAATAAGGGTGACTATAAGAAAATGATTTACAATCTTCTTC
CAGGCCCTAACAAGATGATTCCCAAAGTTTTTTTGTCCAGTAAAACAGGGGTCGAAA
CTTACAAGCCCAGTGCCTATATCCTTGAAGGGTACAAGCAGAATAAGCACATCAAA
TCCTCGAAAGACTTTGATATTACATTTTGTCATGACTTAATCGATTATTTTAAGAACT
GTATCGCAATCCATCCAGAATGGAAGAACTTCGGGTTTGATTTCTCTGATACTTCCA
CGTATGAGGATATTTCCGGGTTCTACCGCGAAGTAGAGCTTCAGGGCTATAAAATTG
ACTGGACATATATTTCAGAAAAAGACATCGATCTGTTACAAGAAAAAGGACAGTTG
TATCTGTTTCAAATCTATAATAAGGATTTCTCCAAAAAGTCAACTGGAAATGATAAC
TTACATACAATGTATCTGAAAAATCTTTTTAGTGAAGAGAATTTGAAGGATATCGTG
CTGAAGTTAAATGGCGAAGCAGAGATCTTCTTCCGCAAGTCCTCGATCAAGAATCCT
ATCATCCACAAGAAAGGTAGTATTCTGGTTAACCGCACGTACGAGGCCGAGGAAAA
AGACCAGTTCGGTAATATCCAGATTGTACGTAAGAATATTCCTGAAAATATTTACCA
GGAATTATACAAGTATTTTAACGACAAATCGGATAAGGAGCTTTCAGATGAGGCCG
CAAAGTTGAAGAACGTCGTAGGACACCATGAGGCCGCTACGAATATCGTCAAGGAC
TACCGCTATACGTATGACAAGTACTTCCTGCACATGCCTATTACTATCAATTTCAAA
GCTAATAAAACAGGATTCATCAATGATCGTATCCTTCAGTACATTGCCAAAGAAAAA
GATCTGCACGTAATCGGAATCGACCGTGGCGAACGTAATCTGATTTACGTATCAGTT
ATCGACACATGTGGTAACATCGTGGAGCAGAAATCTTTTAACATTGTTAACGGCTAT
GATTATCAGATTAAGCTTAAACAGCAGGAGGGGGCACGCCAAATCGCTCGTAAAGA
ATGGAAGGAGATTGGAAAGATTAAAGAGATTAAAGAGGGGTACCTTTCGCTGGTTA
TTCACGAAATTTCCAAGATGGTGATTAAGTACAATGCAATCATCGCGATGGAAGATC
TTAGTTACGGATTCAAAAAGGGACGCTTCAAAGTTGAGCGTCAGGTCTACCAGAAA
TTTGAAACGATGCTGATTAACAAATTGAATTACTTGGTATTCAAAGATATCTCAATT
ACTGAAAATGGTGGCTTATTAAAGGGTTACCAGCTTACCTATATCCCGGATAAGCTG
AAGAACGTGGGCCATCAATGCGGCTGCATCTTTTACGTCCCTGCCGCATATACCTCT
AAAATTGACCCCACCACCGGATTCGTAAATATTTTTAAATTCAAGGACCTGACGGTG
GACGCCAAGCGCGAATTCATCAAAAAATTCGACTCAATCCGCTATGATTCCGAAAA
AAATCTTTTCTGCTTTACGTTCGATTATAATAACTTCATTACCCAAAACACGGTGATG
TCAAAATCGTCCTGGAGCGTGTATACTTATGGAGTGCGTATCAAGCGCCGCTTTGTT
AATGGGCGCTTCAGTAACGAAAGCGATACCATCGACATTACCAAAGACATGGAGAA
GACGCTTGAAATGACGGATATCAATTGGCGTGACGGACACGATCTTCGTCAGGATAT
CATCGACTACGAGATTGTGCAACATATCTTTGAGATTTTCCGTTTAACTGTTCAAATG
CGTAACTCCTTGTCCGAATTGGAAGACCGTGATTACGACCGCTTGATTTCACCAGTG
CTTAACGAGAATAACATCTTCTACGACTCCGCCAAAGCAGGCGATGCCCTGCCAAA
GGACGCTGATGCAAATGGTGCATACTGTATCGCGTTGAAGGGCTTATACGAGATTAA
GCAAATCACCGAAAATTGGAAAGAGGATGGAAAGTTCAGTCGCGATAAGCTGAAGA
TCTCTAATAAAGATTGGTTTGACTTTATCCAGAACAAACGTTATTTA
SEQ ID NO: 27
ATGAACAACGGTACCAATAATTTCCAAAATTTCATCGGAATCTCATCCTTGCAAAAA
ACCTTGCGCAATGCTTTGATCCCCACCGAAACCACGCAGCAGTTCATCGTGAAAAAC
GGCATTATCAAAGAGGATGAGTTGCGCGGGGAAAACCGTCAAATTCTTAAGGATAT
CATGGACGATTACTACCGTGGGTTTATCAGTGAGACCCTGTCAAGCATTGACGACAT
TGACTGGACCAGCTTATTTGAGAAGATGGAGATTCAATTAAAGAACGGGGACAATA
AGGACACGCTTATCAAAGAGCAGACAGAATACCGTAAAGCGATTCATAAGAAATTT
GCAAATGACGATCGCTTCAAGAACATGTTTTCAGCAAAATTAATCAGCGACATCCTT
CCCGAATTTGTGATTCATAATAACAACTATTCGGCTAGCGAAAAAGAGGAGAAAAC
TCAGGTTATTAAGCTTTTCTCGCGTTTTGCCACTTCGTTCAAAGACTATTTTAAGAAT
CGCGCAAACTGCTTTTCGGCTGATGATATTTCCAGTTCTAGCTGCCATCGTATCGTTA
ACGATAATGCTGAGATTTTCTTCTCTAATGCCCTGGTGTATCGTCGTATCGTTAAATC
TTTGAGCAACGACGATATTAATAAGATTTCAGGCGACATGAAGGATTCTTTAAAGGA
GATGTCTTTAGAAGAGATTTATTCCTATGAGAAATATGGCGAGTTTATCACCCAAGA
AGGAATTTCGTTCTACAACGACATCTGTGGCAAAGTGAACAGCTTCATGAATTTATA
CTGCCAAAAGAATAAGGAGAATAAAAATTTATATAAACTGCAGAAACTGCATAAGC
AAATTCTTTGCATTGCAGACACCTCTTATGAAGTTCCTTATAAGTTTGAATCGGACG
AGGAGGTATATCAGAGTGTGAACGGGTTCCTGGACAATATTTCATCCAAGCATATTG
TTGAACGTTTACGCAAAATTGGAGACAATTACAATGGGTATAACCTTGACAAAATTT
ACATCGTGTCGAAGTTTTACGAATCGGTAAGCCAGAAGACCTATCGTGACTGGGAA
ACTATCAATACCGCCTTAGAAATTCATTACAACAATATTCTTCCTGGTAACGGCAAA
AGCAAAGCCGATAAGGTAAAGAAGGCTGTCAAGAACGACCTGCAAAAGTCTATCAC
AGAGATCAACGAGTTAGTCTCTAACTACAAATTATGTTCCGACGACAATATTAAAGC
CGAAACCTACATCCATGAGATCTCACACATTCTTAACAATTTTGAGGCCCAGGAGCT
GAAATATAACCCAGAAATTCACCTTGTAGAGAGCGAATTAAAAGCCTCCGAGCTGA
AGAACGTTTTGGATGTAATCATGAACGCATTTCATTGGTGCAGCGTATTTATGACAG
AGGAGTTGGTCGACAAGGACAATAACTTTTACGCCGAGCTTGAAGAAATCTACGAT
GAAATTTACCCGGTAATTAGTTTATATAATTTAGTTCGCAACTACGTAACTCAGAAA
CCCTACAGTACCAAGAAGATTAAATTGAACTTTGGGATCCCGACACTTGCTGACGGT
TGGAGTAAATCAAAAGAATACTCCAATAATGCAATTATCCTGATGCGCGACAATCTT
TACTACTTGGGGATCTTTAACGCAAAGAACAAACCAGATAAGAAAATCATCGAGGG
CAACACCAGCGAGAATAAAGGCGATTACAAGAAAATGATCTATAATCTTTTGCCGG
GACCGAACAAAATGATCCCAAAGGTTTTCCTGTCGTCGAAAACGGGAGTCGAGACA
TATAAACCATCTGCGTACATCTTGGAAGGTTACAAACAGAATAAGCATATTAAGTCT
AGTAAAGACTTCGACATCACCTTTTGTCATGACCTGATTGATTATTTCAAGAACTGT
ATTGCTATCCATCCAGAATGGAAAAACTTCGGATTTGACTTCTCCGATACTAGCACC
TACGAAGACATTTCGGGTTTTTATCGCGAAGTAGAGCTTCAAGGGTACAAAATTGAT
TGGACATATATTAGCGAGAAAGACATTGATTTGCTTCAAGAGAAGGGACAGTTATA
TTTATTCCAGATCTACAACAAAGACTTCTCGAAGAAATCCACCGGTAATGATAATCT
TCACACTATGTACCTGAAGAATTTATTTTCAGAGGAAAATCTGAAGGACATTGTACT
TAAACTTAATGGAGAAGCCGAAATCTTCTTCCGCAAGAGTTCCATTAAAAATCCGAT
TATTCATAAAAAGGGAAGTATCCTTGTGAACCGCACGTATGAGGCCGAAGAGAAGG
ATCAGTTTGGGAATATTCAAATTGTCCGCAAAAACATCCCCGAGAACATCTACCAGG
AACTGTATAAATACTTTAATGATAAATCTGATAAAGAGTTATCAGACGAGGCTGCCA
AACTGAAAAACGTAGTCGGTCATCATGAGGCAGCGACCAATATTGTAAAGGACTAC
CGTTACACCTACGACAAGTATTTCCTTCACATGCCGATCACGATTAATTTTAAGGCT
AACAAGACCGGCTTTATCAATGACCGCATCTTGCAGTACATCGCGAAAGAGAAAGA
TTTACACGTCATCGGAATTGATCGTGGAGAGCGTAATCTTATCTACGTCAGCGTCAT
CGACACCTGTGGAAACATTGTGGAACAAAAAAGTTTTAATATCGTAAACGGCTACG
ACTATCAAATTAAACTTAAACAGCAAGAGGGAGCTCGCCAGATCGCTCGCAAAGAG
TGGAAAGAGATTGGGAAAATTAAAGAAATTAAAGAGGGTTACCTGTCGCTGGTAAT
TCACGAAATCTCGAAAATGGTCATCAAATATAATGCAATTATCGCTATGGAGGATCT
GTCCTACGGGTTCAAGAAGGGACGTTTTAAAGTAGAGCGCCAGGTGTATCAAAAAT
TCGAAACCATGTTGATCAATAAGCTTAACTATTTGGTCTTCAAAGATATTTCGATTAC
GGAGAACGGAGGTTTGTTGAAAGGATATCAGCTGACGTATATCCCAGACAAGTTGA
AAAACGTGGGGCATCAATGTGGATGTATTTTCTATGTGCCCGCGGCCTACACGAGTA
AGATCGATCCTACCACTGGTTTCGTCAACATTTTCAAATTTAAAGATCTTACCGTGG
ATGCGAAGCGCGAATTTATTAAGAAATTTGATAGCATTCGCTATGATTCCGAAAAGA
ACCTGTTCTGTTTTACGTTCGACTATAACAATTTCATTACCCAAAACACGGTGATGA
GCAAATCCTCTTGGTCAGTTTATACATACGGTGTACGTATCAAACGCCGTTTCGTTA
ACGGACGCTTTTCCAATGAGTCTGATACAATCGATATCACGAAAGATATGGAAAAA
ACATTAGAGATGACTGATATCAACTGGCGTGACGGGCACGACCTGCGTCAAGACAT
TATTGACTACGAGATTGTGCAGCATATCTTCGAAATCTTTCGCTTAACTGTGCAAAT
GCGTAACTCGTTATCCGAGTTAGAAGACCGTGACTACGATCGCCTGATTTCACCCGT
CTTGAACGAAAATAACATCTTCTACGATTCCGCGAAGGCTGGGGACGCATTGCCCAA
GGACGCAGACGCGAATGGAGCGTACTGTATTGCGCTTAAAGGATTATATGAAATCA
AGCAGATCACCGAAAATTGGAAGGAGGACGGGAAGTTCTCACGCGACAAACTGAA
GATTTCAAATAAGGACTGGTTCGATTTCATTCAGAATAAGCGTTACCTG
SEQ ID NO: 28
TGAATAATGGTACGAACAACTTTCAGAACTTCATCGGCATCTCCAGCCTTCAAAAGA
CTTTACGCAACGCATTGATTCCCACGGAGACTACGCAACAGTTTATCGTAAAAAATG
GTATTATCAAAGAAGATGAATTACGCGGGGAGAATCGCCAGATTCTTAAGGACATT
ATGGACGATTATTACCGTGGATTCATCAGTGAGACACTGAGCTCCATTGATGACATC
GACTGGACGTCATTGTTTGAAAAGATGGAAATCCAGTTGAAAAATGGCGATAACAA
AGATACATTGATTAAAGAGCAGACAGAGTACCGCAAAGCAATTCACAAGAAATTCG
CCAATGATGATCGTTTTAAGAACATGTTTAGTGCCAAGCTTATTTCGGATATCTTACC
CGAATTCGTGATTCACAACAACAATTATTCGGCAAGTGAGAAAGAGGAAAAGACCC
AGGTTATCAAATTGTTTTCGCGCTTCGCCACTTCGTTCAAAGATTATTTCAAGAACCG
TGCAAACTGTTTCTCCGCTGACGACATCAGTTCCAGCTCATGCCACCGTATTGTAAA
TGACAATGCGGAGATCTTTTTCAGTAATGCCTTAGTATATCGTCGCATTGTAAAGAG
CTTATCTAATGATGACATTAACAAGATCTCGGGTGATATGAAGGACTCACTTAAGGA
GATGAGTCTGGAAGAGATCTACTCCTACGAAAAATACGGGGAATTCATCACCCAGG
AGGGAATTTCATTCTACAACGATATCTGCGGCAAAGTTAACTCCTTTATGAATCTGT
ACTGTCAAAAGAACAAGGAGAATAAAAACCTGTATAAATTGCAGAAACTTCATAAA
CAAATTTTGTGTATCGCAGACACGAGTTATGAAGTACCTTATAAATTCGAATCCGAC
GAAGAGGTATATCAGTCCGTAAATGGGTTCCTGGACAATATCAGTAGTAAGCACATT
GTGGAACGCTTACGCAAAATTGGAGACAATTACAACGGGTATAACCTGGACAAAAT
CTACATCGTATCCAAATTTTATGAAAGCGTGTCTCAAAAAACTTATCGTGATTGGGA
AACAATCAACACGGCTCTTGAGATCCATTACAATAACATCTTGCCGGGTAACGGCAA
ATCGAAGGCAGACAAAGTTAAAAAAGCAGTTAAGAACGACTTACAGAAAAGCATTA
CGGAGATTAACGAGTTAGTAAGTAATTACAAATTATGCTCCGACGATAATATCAAA
GCTGAAACCTACATCCATGAAATTAGCCACATTTTGAACAATTTCGAAGCGCAGGAG
CTGAAATATAACCCTGAAATCCATCTGGTAGAGTCTGAGTTGAAGGCGTCAGAACTG
AAAAACGTTCTTGACGTCATCATGAATGCCTTTCACTGGTGTAGTGTTTTTATGACTG
AGGAGCTTGTAGATAAGGACAACAACTTCTATGCTGAACTTGAAGAGATCTACGAT
GAAATCTACCCCGTAATCAGTCTGTATAATTTAGTTCGTAACTACGTCACGCAGAAA
CCCTATTCGACTAAGAAAATTAAGCTGAACTTTGGGATCCCTACTTTGGCAGACGGG
TGGAGCAAGAGTAAAGAATACAGTAATAATGCAATTATCTTGATGCGCGATAACTT
ATATTACTTAGGTATTTTCAATGCTAAGAACAAACCTGATAAGAAGATTATCGAAGG
AAATACGAGTGAGAATAAGGGAGACTACAAAAAGATGATTTACAACTTGCTGCCAG
GGCCTAATAAGATGATTCCAAAAGTTTTTCTGTCGAGCAAGACAGGGGTTGAAACTT
ATAAGCCATCCGCTTATATCCTTGAGGGGTACAAGCAGAATAAGCATATCAAGTCCT
CCAAAGATTTTGATATTACATTTTGCCACGACTTAATTGATTACTTCAAGAACTGCAT
CGCAATCCATCCCGAATGGAAGAATTTCGGCTTCGATTTCTCAGATACGTCCACGTA
TGAGGATATCTCAGGCTTTTACCGCGAAGTTGAGCTGCAAGGTTATAAAATTGATTG
GACATACATCTCCGAAAAAGACATTGATCTTTTACAGGAAAAGGGCCAATTATACTT
ATTTCAAATCTATAACAAAGATTTTAGCAAGAAGTCCACAGGTAATGATAACCTGCA
TACGATGTATTTGAAAAATCTTTTCAGTGAAGAGAATTTGAAGGATATCGTCCTGAA
GCTGAACGGTGAGGCTGAGATCTTCTTCCGCAAATCGTCTATCAAAAACCCCATCAT
TCACAAAAAGGGAAGTATCTTAGTAAACCGCACTTATGAAGCGGAGGAAAAGGATC
AGTTCGGGAACATCCAGATCGTGCGCAAGAACATTCCAGAAAACATCTATCAGGAA
CTTTACAAATATTTCAATGACAAGTCTGATAAAGAATTATCAGACGAGGCGGCGAA
ACTTAAAAATGTTGTTGGACACCACGAAGCAGCGACGAATATTGTAAAGGATTATC
GCTACACATACGATAAATACTTTTTGCACATGCCAATCACCATTAACTTTAAGGCGA
ACAAGACAGGTTTCATTAACGACCGTATTCTGCAATATATCGCAAAGGAAAAAGAC
CTGCACGTTATTGGGATCGATCGTGGCGAACGCAATTTGATCTACGTAAGCGTTATC
GACACTTGCGGAAATATCGTTGAACAAAAAAGCTTTAATATCGTCAATGGATACGAT
TACCAAATCAAGCTGAAACAACAAGAAGGGGCACGTCAGATCGCTCGTAAAGAATG
GAAAGAGATTGGTAAGATCAAAGAGATTAAAGAAGGGTATCTTTCTTTAGTAATTC
ACGAGATTTCGAAAATGGTTATTAAATACAATGCGATTATTGCTATGGAAGACTTAA
GCTACGGCTTTAAGAAAGGTCGCTTCAAAGTGGAGCGCCAAGTGTATCAGAAGTTT
GAAACGATGTTGATTAACAAATTAAATTACCTGGTCTTTAAGGACATCAGTATCACA
GAAAATGGGGGGTTGCTTAAAGGGTACCAGCTTACATACATCCCTGATAAACTGAA
AAATGTCGGTCATCAGTGCGGATGTATCTTCTATGTACCAGCAGCCTATACCAGTAA
GATTGACCCTACTACTGGCTTTGTGAATATTTTTAAATTCAAGGATTTAACCGTGGAC
GCCAAGCGTGAATTTATTAAAAAATTTGATTCGATTCGCTACGACAGTGAGAAAAAC
CTTTTCTGCTTTACCTTTGACTACAACAATTTTATTACCCAGAACACCGTAATGTCAA
AGAGTTCGTGGTCTGTATATACCTACGGTGTTCGCATCAAGCGCCGCTTCGTAAACG
GGCGTTTCAGTAACGAATCTGACACCATCGACATCACTAAAGATATGGAGAAGACA
TTGGAAATGACGGACATTAATTGGCGTGATGGCCATGACTTACGTCAGGACATTATT
GATTACGAAATTGTGCAGCATATCTTCGAGATTTTCCGTTTGACAGTTCAGATGCGC
AACTCACTGAGTGAGTTAGAAGATCGCGATTACGACCGTCTGATCTCACCGGTCCTT
AATGAAAACAACATTTTCTACGACTCAGCAAAGGCGGGTGATGCCCTGCCAAAGGA
TGCGGACGCTAATGGCGCCTACTGCATCGCCCTGAAAGGATTGTATGAAATTAAGCA
GATTACAGAAAATTGGAAGGAAGATGGTAAATTTAGCCGTGATAAATTAAAAATCT
CGAACAAGGATTGGTTCGATTTTATTCAGAACAAACGTTATTTG
SEQ ID NO: 29
ATGAACAATGGAACAAATAATTTTCAAAATTTTATCGGCATCTCAAGTCTTCAAAAA
ACCCTTCGCAATGCCCTGATTCCAACTGAAACAACCCAGCAATTTATCGTCAAGAAC
GGCATCATTAAGGAAGACGAGTTACGCGGGGAGAACCGTCAAATCCTGAAAGATAT
CATGGATGACTACTATCGTGGGTTCATTTCGGAAACCTTGTCTTCAATCGACGACAT
TGACTGGACGAGTCTTTTCGAGAAAATGGAAATTCAGCTTAAAAATGGAGACAACA
AGGATACTCTGATTAAGGAACAGACAGAATATCGCAAAGCTATCCACAAAAAGTTC
GCTAATGATGATCGTTTCAAAAATATGTTTTCTGCTAAATTGATTTCCGATATCTTGC
CTGAATTTGTAATCCACAACAACAATTATTCTGCTTCCGAGAAGGAAGAGAAGACCC
AGGTCATTAAATTATTCAGCCGCTTTGCAACCAGCTTTAAAGACTACTTTAAGAATC
GCGCTAACTGCTTTTCGGCGGATGACATCTCATCATCATCATGCCACCGCATTGTGA
ACGACAATGCGGAGATCTTCTTTTCGAATGCGTTAGTTTATCGTCGCATTGTCAAAA
GTCTTAGCAATGATGACATCAACAAGATCTCAGGAGACATGAAAGATTCCTTAAAG
GAGATGTCTCTTGAGGAAATCTATTCGTATGAGAAATACGGCGAGTTCATTACCCAG
GAAGGTATTAGTTTCTACAATGATATCTGCGGCAAAGTAAATTCTTTTATGAATCTG
TATTGCCAAAAAAACAAAGAAAACAAGAATCTTTATAAGTTACAAAAGTTACATAA
GCAAATTCTGTGCATCGCTGATACATCTTATGAGGTACCCTACAAATTTGAAAGTGA
TGAGGAGGTCTATCAGAGTGTCAACGGCTTCTTAGACAACATCTCTTCCAAACATAT
CGTGGAACGCCTGCGTAAAATCGGAGATAACTACAACGGATATAACTTAGATAAAA
TCTACATCGTGTCCAAGTTTTATGAAAGTGTGAGCCAAAAAACATATCGTGACTGGG
AAACCATTAACACCGCATTGGAAATTCACTATAACAACATTTTGCCAGGCAACGGG
AAAAGTAAGGCGGACAAAGTTAAGAAAGCAGTTAAAAATGACCTGCAAAAAAGCA
TCACTGAAATTAACGAATTGGTATCGAATTACAAATTATGTAGCGACGATAATATCA
AAGCAGAAACTTACATTCACGAGATTAGTCACATTTTAAATAACTTCGAGGCCCAGG
AATTGAAATACAATCCCGAAATTCATTTGGTTGAATCAGAACTGAAAGCATCAGAGT
TGAAAAATGTGTTAGATGTCATTATGAATGCGTTTCATTGGTGCTCTGTGTTCATGAC
CGAGGAACTGGTTGATAAAGATAACAACTTTTACGCTGAATTGGAGGAGATTTACG
ATGAGATTTACCCGGTCATTTCGCTTTATAACTTAGTGCGCAATTATGTGACGCAGA
AACCATATTCCACGAAGAAAATCAAACTTAATTTTGGCATCCCTACTCTGGCTGATG
GTTGGTCGAAATCGAAAGAGTACAGCAACAACGCGATCATTCTTATGCGTGACAAT
CTTTACTATTTGGGCATTTTTAATGCCAAGAATAAGCCAGATAAGAAAATCATTGAG
GGGAATACTTCCGAGAATAAGGGGGATTACAAAAAGATGATCTATAACTTGCTGCC
CGGCCCCAACAAAATGATTCCTAAGGTTTTCTTGTCAAGCAAGACGGGCGTCGAAAC
ATATAAGCCGTCAGCTTATATTCTGGAAGGCTATAAACAGAATAAGCACATCAAGTC
TTCCAAGGACTTTGACATCACTTTTTGCCACGATTTGATCGACTACTTTAAGAACTGT
ATTGCGATTCATCCGGAATGGAAGAACTTCGGTTTCGACTTTTCCGATACCTCAACA
TACGAGGATATCAGCGGCTTCTACCGTGAAGTCGAGCTTCAAGGCTACAAGATCGAT
TGGACATATATTTCAGAGAAGGACATTGATTTGTTACAAGAGAAAGGTCAACTTTAC
TTATTTCAGATCTATAACAAAGACTTTTCGAAGAAATCGACAGGAAACGATAACTTA
CACACTATGTATTTAAAAAATCTGTTTTCGGAGGAAAACCTGAAAGATATTGTGCTG
AAACTTAACGGCGAGGCAGAGATCTTTTTCCGTAAAAGCTCAATCAAGAATCCTATC
ATCCATAAAAAAGGTAGTATTCTTGTCAACCGCACATATGAAGCGGAGGAGAAGGA
CCAATTCGGAAACATCCAAATTGTCCGTAAGAATATTCCGGAGAACATTTACCAAGA
GTTGTATAAATACTTTAACGATAAGTCAGATAAGGAACTTAGCGATGAGGCGGCGA
AGCTTAAAAACGTAGTTGGGCATCATGAAGCTGCTACCAACATTGTAAAAGATTACC
GTTACACCTATGACAAGTATTTCTTGCACATGCCCATTACGATCAATTTCAAAGCAA
ATAAGACAGGCTTTATCAATGATCGCATCCTGCAGTACATTGCTAAAGAGAAGGATT
TGCATGTTATCGGTATTGATCGCGGAGAGCGCAATTTGATCTACGTCTCCGTAATCG
ACACTTGCGGTAACATTGTTGAGCAGAAGTCGTTCAACATCGTTAATGGTTATGATT
ACCAAATCAAGCTGAAGCAGCAAGAGGGTGCCCGCCAGATCGCGCGTAAGGAATGG
AAAGAAATCGGGAAAATTAAAGAGATCAAAGAAGGCTATTTGTCTCTGGTAATTCA
CGAAATCAGCAAGATGGTGATCAAGTATAACGCGATCATTGCGATGGAGGATCTTT
CTTATGGCTTCAAGAAAGGGCGCTTTAAAGTCGAACGCCAGGTCTACCAGAAATTTG
AGACAATGCTTATCAACAAGCTTAACTATCTTGTATTTAAGGATATTTCCATCACTG
AGAACGGAGGACTTTTAAAGGGGTACCAACTGACGTACATTCCTGATAAGCTGAAG
AACGTTGGTCATCAATGCGGATGCATCTTCTATGTGCCAGCGGCTTACACCTCCAAA
ATCGATCCCACTACAGGCTTTGTCAATATCTTCAAATTCAAGGATTTGACCGTTGAC
GCGAAGCGCGAGTTTATCAAGAAGTTTGATAGCATTCGCTACGACAGCGAAAAAAA
TTTATTTTGTTTTACTTTCGACTACAATAACTTTATTACTCAGAACACTGTCATGTCA
AAGAGTTCGTGGAGTGTCTACACGTACGGAGTACGTATTAAGCGCCGTTTCGTCAAC
GGACGCTTCTCAAACGAAAGCGACACGATCGACATCACCAAAGACATGGAAAAAAC
TCTTGAGATGACGGATATCAATTGGCGCGACGGCCATGACCTGCGTCAGGATATCAT
TGATTACGAGATCGTTCAGCACATCTTCGAAATCTTCCGCCTTACCGTCCAGATGCG
CAACAGTTTAAGCGAGCTTGAAGACCGCGACTACGATCGTTTGATTAGCCCCGTTCT
GAACGAGAATAATATTTTCTACGACAGCGCAAAGGCCGGTGATGCTTTGCCAAAGG
ACGCAGACGCGAATGGAGCCTACTGCATCGCCCTGAAGGGCTTATATGAGATTAAG
CAAATTACCGAAAATTGGAAGGAAGATGGTAAGTTCTCCCGTGATAAGCTTAAAAT
TAGCAATAAGGATTGGTTCGACTTCATCCAGAACAAACGTTACCTG
SEQ ID NO: 30
ATGAACAACGGAACAAACAATTTCCAAAACTTCATCGGTATCTCTTCGTTGCAGAAG
ACTCTGCGTAATGCTTTGATCCCGACGGAGACAACCCAACAATTTATCGTCAAAAAC
GGTATTATTAAGGAGGACGAGTTACGTGGAGAAAATCGTCAAATCCTTAAGGACAT
CATGGACGATTATTATCGCGGGTTTATTTCTGAAACCCTGAGCAGTATCGATGATAT
CGACTGGACCTCACTTTTTGAGAAAATGGAGATCCAGTTGAAGAACGGTGATAACA
AAGACACTCTGATCAAAGAGCAAACTGAATACCGCAAGGCAATTCACAAAAAGTTC
GCCAACGACGACCGTTTCAAGAATATGTTCTCAGCTAAGTTAATCAGCGACATTTTG
CCAGAGTTCGTTATCCACAACAATAATTATAGTGCTTCAGAGAAGGAGGAAAAAAC
CCAAGTGATTAAACTTTTTTCGCGCTTTGCAACCTCATTCAAGGACTACTTCAAGAAT
CGCGCGAATTGCTTCAGTGCGGACGACATTTCTTCTTCAAGTTGCCATCGTATCGTTA
ACGATAACGCGGAAATTTTCTTCTCTAATGCTTTGGTGTATCGCCGCATTGTAAAATC
GCTTAGTAACGATGACATTAATAAGATCTCAGGTGATATGAAAGATTCATTGAAGG
AAATGAGCTTGGAAGAGATTTACAGTTACGAAAAATATGGAGAATTTATTACTCAG
GAAGGCATCTCATTCTATAACGATATCTGCGGGAAGGTAAATTCGTTTATGAACTTA
TATTGCCAGAAAAATAAAGAGAATAAAAATTTGTATAAGCTTCAGAAGTTGCACAA
ACAGATCCTGTGCATTGCAGACACCTCGTATGAGGTTCCGTATAAATTTGAGTCCGA
TGAAGAAGTGTATCAGTCTGTGAATGGTTTCTTAGATAATATCTCTTCCAAGCATATT
GTCGAACGCCTGCGCAAAATTGGTGATAACTATAACGGATACAATCTGGATAAAAT
TTACATCGTTTCTAAATTTTACGAGTCAGTCTCGCAGAAGACCTACCGCGACTGGGA
AACAATTAACACGGCATTGGAGATTCACTACAATAATATCTTGCCTGGTAACGGTAA
GTCTAAGGCAGATAAGGTAAAAAAAGCTGTGAAAAACGACCTTCAGAAAAGCATCA
CGGAGATTAATGAGCTGGTGAGTAATTACAAATTATGTTCAGACGATAATATTAAAG
CTGAAACGTATATCCATGAAATCTCGCATATCTTGAACAACTTCGAGGCCCAAGAAC
TTAAATATAACCCCGAAATCCATTTAGTCGAGTCTGAATTGAAAGCGTCGGAATTAA
AAAACGTCTTAGACGTCATTATGAACGCGTTTCACTGGTGTTCAGTTTTCATGACCG
AAGAGCTGGTCGACAAAGACAACAACTTCTATGCGGAATTGGAGGAAATCTATGAT
GAAATCTACCCTGTTATTTCACTGTATAACCTTGTGCGCAACTATGTCACTCAGAAG
CCGTATTCGACCAAAAAAATTAAATTGAATTTCGGTATCCCTACTCTTGCAGACGGA
TGGAGTAAAAGCAAGGAATACAGTAATAACGCCATTATTCTTATGCGCGACAATTTA
TACTACCTGGGCATCTTTAACGCAAAGAATAAGCCGGATAAGAAGATTATTGAGGG
TAACACCAGTGAGAACAAGGGCGACTATAAGAAGATGATCTATAACTTATTGCCAG
GTCCAAATAAAATGATCCCAAAAGTATTCTTATCATCAAAGACGGGAGTTGAAACCT
ATAAGCCTAGTGCCTATATTCTTGAGGGATATAAACAGAACAAGCACATTAAGTCGT
CTAAGGATTTTGACATTACGTTCTGCCATGACTTAATCGACTATTTTAAAAACTGTAT
TGCGATTCACCCCGAATGGAAGAATTTTGGATTCGATTTTTCGGATACCTCGACCTA
TGAAGATATTTCGGGATTTTATCGTGAAGTGGAGTTGCAAGGCTATAAAATCGATTG
GACCTATATCTCAGAAAAAGACATTGATTTATTACAGGAAAAGGGACAACTGTACC
TTTTCCAAATTTATAACAAGGACTTTTCTAAAAAGTCCACAGGAAATGATAACCTTC
ACACCATGTACCTGAAGAACCTTTTCTCAGAGGAAAACCTGAAGGACATTGTCCTTA
AGTTAAATGGAGAAGCGGAGATCTTTTTCCGTAAATCTAGTATCAAGAATCCGATTA
TCCATAAAAAAGGTTCGATTTTGGTAAATCGCACCTATGAAGCGGAAGAGAAAGAT
CAATTTGGTAACATCCAGATCGTGCGCAAGAATATCCCGGAGAACATTTACCAAGA
GCTGTATAAGTACTTCAATGATAAGTCTGATAAGGAACTGTCAGATGAAGCTGCGA
AATTGAAGAACGTGGTTGGGCATCATGAAGCCGCTACCAATATCGTCAAGGATTAC
CGTTATACCTATGACAAATATTTCTTACACATGCCGATTACGATCAATTTTAAGGCA
AACAAGACAGGATTCATCAACGACCGTATCTTGCAGTATATTGCCAAAGAGAAGGA
TCTGCATGTGATCGGTATTGACCGCGGGGAGCGCAATTTAATCTATGTATCGGTGAT
CGATACTTGTGGTAACATCGTAGAACAAAAGAGCTTTAACATCGTGAATGGTTACGA
CTATCAGATCAAGCTGAAACAACAGGAAGGAGCCCGCCAGATCGCTCGCAAGGAAT
GGAAAGAAATCGGGAAAATTAAGGAAATCAAGGAAGGCTACCTTTCATTGGTCATT
CACGAAATTTCGAAAATGGTAATTAAGTACAACGCGATCATCGCCATGGAGGACCT
TTCGTACGGATTTAAGAAGGGTCGTTTCAAAGTTGAGCGCCAGGTATACCAAAAATT
CGAGACTATGCTTATCAACAAACTTAACTACTTGGTCTTTAAGGACATTTCTATTACC
GAAAACGGCGGCTTACTTAAAGGCTATCAATTGACATATATTCCCGACAAACTGAA
GAATGTTGGACATCAATGCGGGTGTATTTTCTATGTGCCGGCAGCTTACACTAGTAA
GATCGACCCTACAACCGGGTTCGTAAACATTTTTAAATTCAAAGACTTAACAGTCGA
TGCGAAGCGTGAATTTATTAAGAAGTTTGATAGTATCCGCTATGACAGTGAAAAGA
ACTTGTTTTGCTTTACGTTCGACTACAATAACTTTATTACACAGAACACGGTCATGTC
TAAATCATCATGGTCGGTTTACACATATGGGGTGCGCATCAAGCGTCGCTTTGTAAA
TGGCCGTTTTAGTAATGAGAGCGACACAATCGACATCACAAAGGATATGGAGAAAA
CTCTTGAGATGACAGACATCAATTGGCGTGACGGTCATGACTTACGCCAAGATATCA
TCGACTACGAAATCGTACAGCATATTTTTGAGATTTTTCGTCTTACTGTGCAAATGCG
TAATTCTTTATCCGAACTGGAAGATCGTGATTACGACCGCTTGATTAGTCCCGTCTTA
AATGAGAACAATATTTTCTATGATTCTGCGAAAGCCGGAGATGCACTGCCCAAAGA
CGCTGATGCCAATGGCGCGTATTGCATTGCATTAAAAGGATTATATGAGATTAAACA
GATTACCGAAAATTGGAAAGAGGACGGTAAATTCTCACGCGATAAATTGAAGATTT
CTAACAAGGACTGGTTCGACTTTATCCAAAATAAACGTTATCTT
SEQ ID NO: 31
ATGAATAACGGTACCAACAACTTTCAGAATTTCATTGGCATTAGCTCGCTTCAAAAA
ACTTTACGCAATGCTCTTATTCCGACTGAGACGACACAACAGTTTATCGTTAAGAAT
GGCATCATCAAAGAAGATGAATTACGCGGAGAAAACCGCCAGATCCTGAAAGACAT
TATGGACGATTATTACCGTGGGTTCATCTCCGAGACGTTGTCATCGATCGATGACAT
CGACTGGACGTCACTTTTTGAAAAAATGGAGATCCAGTTAAAGAACGGTGACAATA
AGGATACATTGATCAAAGAACAGACCGAGTACCGTAAAGCGATTCATAAAAAGTTT
GCGAACGATGATCGCTTCAAGAATATGTTTTCTGCGAAATTAATTTCCGACATTTTA
CCTGAATTTGTTATTCATAATAACAACTACTCGGCGTCTGAGAAAGAGGAGAAAACC
CAAGTGATTAAACTTTTTTCACGTTTCGCAACGTCGTTCAAAGACTATTTTAAAAATC
GTGCTAATTGCTTTAGCGCGGATGACATCAGCTCTAGTTCATGTCATCGCATTGTCA
ACGATAATGCTGAGATCTTTTTCAGTAATGCGTTAGTGTACCGTCGTATTGTGAAGT
CCTTATCTAATGATGATATCAATAAGATCAGCGGGGATATGAAGGACTCACTTAAGG
AGATGAGCTTGGAGGAAATCTATTCCTATGAGAAGTATGGTGAGTTTATTACGCAAG
AAGGAATTAGCTTTTACAACGATATCTGTGGAAAGGTGAATTCGTTTATGAATTTGT
ATTGCCAGAAAAATAAGGAGAACAAGAACCTTTATAAATTGCAAAAGTTACACAAG
CAAATCCTGTGCATTGCAGATACTTCCTACGAGGTGCCTTACAAGTTTGAATCCGAC
GAAGAGGTCTACCAATCTGTAAACGGTTTCTTAGATAATATTAGTTCCAAGCATATT
GTGGAGCGCCTTCGTAAAATTGGCGATAATTACAACGGTTACAATTTAGACAAAATT
TACATTGTCAGTAAATTCTACGAGTCCGTATCTCAAAAGACGTATCGTGATTGGGAG
ACTATCAATACGGCCCTGGAGATCCACTACAACAATATCTTGCCCGGTAATGGTAAG
TCGAAGGCCGATAAAGTTAAGAAAGCGGTGAAAAATGACTTACAGAAGTCAATCAC
CGAAATTAACGAATTGGTGTCCAATTATAAATTGTGTTCAGATGATAATATCAAAGC
CGAGACCTACATTCATGAGATTTCCCATATCTTAAATAATTTCGAGGCGCAAGAGCT
TAAGTATAACCCAGAAATCCACCTGGTAGAATCTGAGTTGAAGGCGTCAGAGTTAA
AAAATGTTTTAGATGTCATTATGAACGCGTTTCACTGGTGCTCCGTATTTATGACGG
AGGAATTAGTAGATAAAGACAACAATTTCTATGCCGAACTTGAGGAAATCTATGAT
GAGATCTATCCCGTCATTAGCCTGTATAACTTGGTCCGCAACTATGTTACCCAAAAA
CCGTACAGTACCAAGAAGATTAAGCTGAATTTCGGCATTCCTACACTGGCTGATGGT
TGGAGTAAATCGAAGGAATATTCGAATAACGCGATTATCTTGATGCGCGACAACTTA
TACTATTTGGGGATCTTTAACGCCAAAAACAAACCGGATAAGAAGATTATTGAGGG
AAACACATCAGAGAACAAAGGCGACTACAAAAAAATGATTTACAACTTGTTACCGG
GGCCTAACAAAATGATCCCGAAGGTGTTCTTATCCAGTAAAACAGGCGTTGAGACCT
ACAAACCTTCCGCATACATCCTGGAAGGGTATAAGCAGAACAAGCACATTAAGTCC
AGCAAGGATTTCGATATTACCTTCTGTCATGATTTAATTGACTATTTCAAGAACTGTA
TTGCAATCCACCCCGAGTGGAAGAACTTCGGATTCGACTTCTCAGATACGAGCACAT
ATGAGGACATCTCGGGGTTCTATCGTGAAGTAGAACTGCAGGGATATAAAATTGATT
GGACATATATTTCCGAAAAAGACATCGACCTTTTACAAGAGAAGGGTCAACTTTACT
TGTTCCAAATTTACAATAAAGACTTCTCAAAAAAAAGCACGGGTAACGATAATTTAC
ACACTATGTATTTAAAGAACCTTTTCTCGGAAGAGAATTTAAAGGATATCGTATTGA
AGTTGAATGGAGAAGCGGAGATCTTCTTCCGTAAGTCCAGTATTAAAAACCCTATTA
TTCACAAGAAGGGATCGATTTTAGTTAACCGCACATACGAGGCCGAAGAGAAGGAC
CAATTTGGGAACATTCAAATTGTCCGCAAAAACATCCCTGAGAACATTTATCAAGAG
CTTTATAAGTACTTTAACGATAAGTCCGATAAGGAATTGTCAGATGAGGCGGCAAA
GTTGAAGAATGTCGTGGGGCATCATGAAGCTGCCACCAACATTGTGAAGGACTACC
GCTACACTTACGACAAATACTTCCTGCACATGCCCATTACGATCAATTTTAAGGCCA
ATAAGACAGGCTTTATTAACGACCGTATTCTTCAATATATCGCTAAGGAGAAGGACC
TTCATGTGATTGGGATCGACCGCGGAGAACGTAATTTAATTTATGTGTCCGTCATCG
ATACGTGTGGAAATATCGTGGAACAGAAATCATTCAATATCGTGAATGGCTATGATT
ACCAGATCAAATTAAAACAGCAGGAGGGCGCTCGCCAAATTGCGCGTAAGGAATGG
AAAGAGATCGGAAAAATCAAAGAAATCAAAGAAGGATATTTGTCATTGGTGATCCA
TGAGATTTCAAAAATGGTAATTAAATATAATGCAATTATCGCAATGGAAGACCTGTC
CTATGGTTTTAAGAAGGGTCGTTTCAAGGTAGAACGCCAAGTGTATCAAAAGTTCGA
GACGATGCTGATCAATAAGCTGAATTATCTTGTGTTTAAGGACATTAGCATCACGGA
AAATGGAGGGCTGTTGAAAGGCTATCAACTGACGTATATCCCTGACAAGCTGAAAA
ATGTTGGCCATCAGTGCGGGTGCATTTTCTACGTCCCCGCGGCGTATACAAGCAAGA
TCGATCCTACTACGGGATTCGTAAATATTTTTAAATTCAAAGACTTAACCGTGGACG
CCAAGCGCGAATTCATTAAGAAGTTTGATAGCATTCGCTACGATTCAGAAAAAAATC
TTTTCTGTTTTACGTTCGATTACAACAATTTTATCACCCAGAACACAGTGATGAGCAA
GTCATCCTGGTCTGTCTATACCTACGGTGTCCGTATCAAACGCCGCTTCGTCAACGG
ACGCTTCTCTAATGAATCTGATACCATTGACATCACCAAGGACATGGAAAAGACACT
TGAGATGACAGATATTAACTGGCGTGACGGACATGACCTGCGTCAGGACATCATCG
ATTATGAGATTGTTCAGCATATCTTCGAGATCTTCCGCCTGACAGTACAAATGCGCA
ATTCACTGTCAGAACTTGAAGACCGCGACTATGACCGCCTGATCTCTCCAGTATTAA
ATGAGAACAATATCTTTTATGACAGTGCTAAGGCCGGCGATGCCCTTCCGAAAGATG
CTGATGCTAACGGAGCTTATTGTATTGCATTAAAGGGTCTTTATGAGATCAAGCAAA
TTACCGAGAATTGGAAGGAGGATGGCAAATTCTCGCGCGACAAACTGAAAATCAGT
AACAAGGACTGGTTCGATTTTATTCAGAATAAACGTTACCTG
SEQ ID NO: 32
ATGAATAACGGAACGAACAACTTCCAGAACTTCATCGGCATCAGTTCTTTACAAAAA
ACCCTGCGTAACGCCCTTATTCCGACTGAGACAACACAACAGTTCATCGTTAAAAAC
GGAATTATCAAAGAGGACGAGTTGCGCGGCGAGAATCGCCAAATTTTGAAAGATAT
TATGGACGACTATTATCGTGGTTTTATTTCAGAAACACTGAGTTCGATTGACGATAT
CGATTGGACGAGCCTGTTTGAGAAAATGGAAATCCAGTTGAAAAATGGCGATAATA
AAGACACTTTAATCAAAGAACAAACCGAGTATCGTAAAGCGATCCATAAAAAGTTC
GCTAATGACGATCGTTTTAAGAATATGTTCAGTGCGAAACTGATTTCAGACATTTTG
CCCGAGTTCGTGATCCATAATAACAACTATTCCGCCTCGGAAAAGGAAGAAAAAAC
CCAGGTGATTAAGCTGTTCAGTCGCTTCGCAACATCTTTCAAGGATTATTTCAAGAA
TCGCGCGAATTGCTTCAGTGCGGACGATATTTCTAGTTCAAGCTGCCATCGTATCGTT
AATGATAACGCGGAGATTTTTTTTAGCAATGCTCTGGTGTACCGCCGCATTGTTAAG
TCACTGTCCAACGATGATATTAACAAGATCTCAGGAGACATGAAAGACTCGCTTAA
AGAGATGAGTCTGGAAGAGATCTATTCTTATGAGAAGTATGGCGAGTTTATTACCCA
AGAAGGAATCTCATTCTACAATGATATTTGTGGAAAGGTGAACAGCTTTATGAATCT
TTACTGCCAAAAAAACAAGGAGAATAAGAATCTTTACAAACTTCAGAAGTTACATA
AACAGATTTTGTGTATTGCGGATACGTCTTATGAAGTCCCCTACAAATTTGAATCGG
ATGAAGAGGTATACCAAAGTGTGAACGGATTCTTGGACAATATTTCTTCTAAACATA
TTGTTGAACGCTTACGTAAGATCGGGGATAACTACAATGGCTACAATCTTGACAAAA
TCTACATTGTTAGCAAATTCTACGAGAGTGTCAGCCAAAAGACGTACCGCGATTGGG
AAACAATTAATACTGCGCTTGAGATTCACTATAATAACATTTTACCAGGCAACGGCA
AGTCCAAGGCGGATAAAGTTAAAAAAGCTGTTAAAAACGATTTGCAAAAATCTATC
ACAGAAATTAACGAGTTAGTTAGTAACTACAAACTGTGCTCCGATGACAACATTAA
GGCTGAGACGTATATCCATGAGATCTCTCACATCTTAAACAATTTTGAAGCTCAAGA
ACTTAAGTACAATCCGGAAATCCACCTGGTGGAATCCGAGCTGAAGGCTAGCGAAC
TGAAGAACGTATTGGACGTGATCATGAACGCGTTCCACTGGTGTTCTGTCTTTATGA
CGGAAGAGCTTGTCGACAAAGATAATAACTTTTACGCGGAACTTGAGGAAATTTAC
GATGAGATTTACCCAGTTATTTCATTGTATAACCTTGTCCGTAATTACGTGACCCAAA
AGCCTTATAGTACGAAAAAAATCAAATTAAATTTTGGAATCCCAACACTGGCTGACG
GTTGGAGCAAATCTAAGGAGTATTCTAATAACGCAATCATCTTAATGCGTGACAACC
TGTATTATTTGGGTATCTTCAATGCCAAAAATAAGCCTGACAAAAAGATTATCGAAG
GAAATACTTCGGAGAATAAGGGGGATTACAAAAAAATGATTTACAATTTGCTGCCC
GGGCCGAACAAGATGATCCCCAAAGTGTTCTTATCCTCGAAGACTGGTGTAGAAAC
ATACAAGCCAAGCGCATACATTCTGGAGGGTTACAAGCAAAACAAACACATCAAAT
CTTCAAAAGACTTTGACATTACATTTTGCCATGATCTTATTGACTACTTCAAAAACTG
CATTGCTATTCACCCCGAGTGGAAGAACTTTGGGTTTGACTTCAGCGACACGTCTAC
GTATGAGGACATCTCCGGGTTCTACCGTGAAGTTGAGTTACAAGGGTATAAGATTGA
CTGGACGTATATTTCAGAGAAAGATATCGATCTTTTGCAGGAAAAGGGCCAGTTATA
TTTATTCCAGATTTACAACAAGGACTTTAGTAAGAAGTCAACAGGAAATGACAACTT
GCATACGATGTATTTGAAAAATCTTTTTTCTGAGGAAAATCTTAAGGACATCGTACT
GAAATTGAATGGCGAGGCTGAAATCTTCTTCCGTAAATCCTCCATTAAGAATCCCAT
TATCCACAAAAAGGGGTCTATCCTGGTGAATCGTACCTACGAGGCAGAGGAGAAGG
ATCAATTCGGAAATATTCAGATTGTTCGTAAGAACATCCCCGAGAACATTTATCAAG
AATTGTATAAGTACTTTAATGACAAATCTGACAAAGAGTTATCCGACGAAGCTGCGA
AACTGAAAAACGTTGTTGGTCACCACGAGGCCGCCACTAATATCGTAAAAGACTAC
CGTTATACCTATGACAAGTACTTTTTGCACATGCCGATCACTATCAACTTCAAGGCG
AATAAGACGGGCTTCATTAACGATCGTATCCTGCAATACATCGCCAAGGAGAAGGA
CCTTCACGTCATTGGGATTGACCGTGGTGAGCGTAACCTGATTTATGTAAGCGTCAT
TGATACCTGCGGTAATATCGTCGAACAGAAAAGTTTCAACATTGTAAATGGATATGA
CTATCAGATCAAACTTAAGCAGCAGGAGGGTGCACGCCAGATTGCCCGCAAGGAAT
GGAAGGAGATTGGGAAGATTAAGGAAATTAAAGAAGGTTACTTATCACTGGTTATT
CACGAGATCAGTAAAATGGTAATCAAATATAACGCGATCATTGCCATGGAGGATCT
GAGCTATGGCTTTAAAAAGGGCCGTTTCAAAGTCGAGCGCCAGGTATATCAAAAGT
TTGAAACAATGCTGATTAACAAATTAAACTATCTGGTTTTCAAAGATATTTCGATCA
CTGAAAATGGCGGGCTGTTGAAGGGATACCAACTTACATACATCCCTGACAAACTG
AAAAATGTCGGTCACCAATGTGGATGTATCTTTTATGTACCAGCAGCGTATACGAGC
AAAATCGATCCAACTACGGGTTTTGTGAACATCTTTAAGTTCAAGGATTTGACAGTA
GATGCCAAACGCGAGTTCATTAAAAAATTTGATTCAATTCGCTACGATTCAGAGAAA
AATCTTTTTTGTTTCACGTTCGATTACAATAATTTCATTACGCAGAACACAGTAATGT
CAAAGTCAAGCTGGTCGGTCTACACGTATGGAGTCCGTATTAAACGTCGTTTTGTAA
ACGGCCGTTTCTCAAATGAATCAGATACAATTGATATTACGAAGGATATGGAGAAG
ACATTAGAGATGACTGACATTAACTGGCGCGACGGACATGATCTTCGTCAGGACATT
ATTGATTATGAGATTGTACAGCATATCTTTGAGATCTTCCGCCTGACCGTTCAGATGC
GCAATTCGTTGTCCGAGTTAGAAGACCGCGATTACGACCGTTTAATCAGTCCCGTCT
TAAACGAAAATAACATCTTCTACGATTCAGCCAAGGCAGGCGATGCCTTGCCAAAG
GATGCTGACGCAAATGGCGCATACTGTATTGCGTTGAAAGGCCTTTATGAAATCAAG
CAAATTACCGAAAACTGGAAAGAAGACGGAAAATTCTCCCGTGATAAGTTGAAAAT
CTCTAATAAGGATTGGTTCGATTTCATCCAAAATAAACGCTATTTG
SEQ ID NO: 33
ATGAACAACGGAACTAATAATTTCCAAAATTTTATAGGCATCTCTTCTTTACAGAAG
ACTCTTCGTAACGCCCTAATCCCGACTGAGACCACACAACAATTCATAGTGAAAAAT
GGGATCATTAAAGAAGACGAGCTGCGTGGGGAGAACAGGCAGATCCTAAAAGACA
TAATGGACGATTATTATAGAGGGTTCATCTCAGAGACATTATCTAGCATCGACGACA
TTGACTGGACCTCCCTGTTTGAAAAAATGGAAATCCAGCTGAAGAATGGTGACAAT
AAAGACACATTAATAAAAGAACAAACAGAGTACAGGAAAGCCATCCACAAGAAGT
TCGCAAACGATGACAGATTCAAAAATATGTTCAGTGCGAAGCTAATATCCGACATCT
TACCAGAGTTTGTAATACACAATAACAATTACAGCGCGAGCGAAAAGGAAGAGAAA
ACGCAAGTAATTAAGCTTTTTAGTAGGTTCGCTACCTCTTTCAAAGATTACTTCAAA
AATCGTGCTAACTGCTTCTCAGCCGACGACATATCTTCAAGTTCCTGTCACCGTATCG
TGAATGATAACGCTGAGATATTCTTCTCAAACGCCCTTGTATACCGTAGGATCGTAA
AGTCCTTATCTAACGATGATATAAACAAGATCAGTGGAGACATGAAAGACAGCCTT
AAAGAGATGTCTCTAGAAGAAATTTACTCCTATGAAAAGTATGGGGAGTTTATAAC
ACAGGAGGGGATCAGCTTCTACAACGACATCTGCGGAAAGGTGAACAGTTTCATGA
ATCTTTACTGCCAGAAGAATAAAGAGAACAAAAATCTTTATAAGCTTCAAAAGTTGC
ACAAACAAATACTGTGCATTGCCGATACATCATATGAGGTCCCCTATAAGTTCGAAT
CTGATGAGGAAGTTTATCAATCTGTTAACGGCTTTCTAGACAATATCAGCTCAAAAC
ACATCGTAGAAAGACTGAGGAAAATAGGTGATAATTATAATGGATACAACTTGGAT
AAAATATATATAGTCTCTAAATTTTACGAGTCAGTATCCCAGAAAACGTATAGGGAT
TGGGAGACCATCAACACGGCGTTAGAGATTCATTACAATAACATCTTACCGGGAAA
CGGAAAAAGTAAGGCGGACAAAGTAAAGAAAGCCGTTAAAAATGACTTACAAAAG
AGTATAACAGAAATAAACGAACTAGTAAGCAACTACAAGCTTTGTTCCGATGATAA
TATCAAGGCCGAGACATATATCCATGAGATCTCCCACATTCTAAACAATTTCGAAGC
GCAAGAACTTAAATATAATCCCGAAATCCACCTGGTGGAAAGTGAACTAAAGGCTA
GTGAGTTAAAGAACGTTCTTGATGTTATCATGAACGCCTTCCATTGGTGCTCTGTTTT
TATGACCGAGGAGTTGGTTGATAAAGATAATAATTTCTACGCTGAATTAGAGGAGAT
ATACGACGAAATCTACCCAGTGATTTCACTATACAACTTGGTCAGGAACTATGTTAC
ACAAAAGCCGTACAGCACTAAGAAAATTAAGCTAAATTTCGGTATCCCCACGTTAG
CCGACGGGTGGAGCAAGTCCAAAGAATATTCCAACAATGCGATTATTTTAATGCGTG
ACAATCTTTATTACCTTGGCATCTTCAATGCCAAAAACAAACCTGACAAAAAGATTA
TAGAAGGTAATACGTCCGAGAACAAAGGCGATTACAAGAAGATGATTTATAACCTA
CTGCCCGGACCAAACAAAATGATCCCCAAAGTTTTTCTTAGTTCTAAAACCGGCGTA
GAGACGTATAAACCTTCTGCCTATATCTTAGAGGGATATAAGCAGAACAAACATATC
AAATCTTCCAAGGACTTTGATATTACATTCTGCCACGATTTAATTGACTACTTCAAAA
ATTGCATAGCGATACATCCGGAGTGGAAGAACTTTGGCTTCGACTTCAGTGATACAT
CCACCTATGAGGATATATCAGGCTTCTATCGTGAGGTCGAATTGCAAGGGTACAAAA
TCGATTGGACGTATATATCCGAGAAAGACATAGACCTTCTTCAAGAAAAGGGGCAG
TTATATTTATTCCAAATATACAACAAGGACTTCAGTAAGAAGTCAACAGGTAATGAC
AACTTACACACCATGTACTTGAAAAATTTATTTTCTGAAGAAAACCTAAAGGACATT
GTACTAAAACTGAACGGGGAGGCAGAAATTTTTTTTAGAAAGAGCAGCATAAAAAA
CCCAATAATTCATAAGAAAGGAAGCATTTTAGTTAATAGGACGTACGAGGCAGAGG
AAAAGGACCAGTTTGGCAATATCCAGATCGTAAGGAAAAATATTCCTGAAAACATA
TATCAGGAACTATATAAATACTTTAACGACAAATCCGACAAAGAATTATCCGACGA
GGCTGCAAAGCTGAAGAACGTCGTAGGGCACCATGAGGCAGCGACTAATATTGTGA
AAGACTATAGGTATACATACGACAAATACTTTCTGCACATGCCCATCACGATTAACT
TCAAGGCGAACAAGACGGGATTCATTAACGACCGTATATTACAATATATTGCTAAG
GAGAAAGATCTGCATGTAATAGGTATCGACAGAGGCGAACGTAATTTAATCTACGT
GTCCGTCATCGACACGTGCGGGAACATCGTAGAGCAAAAGAGTTTTAATATAGTAA
ATGGCTATGATTACCAAATTAAGCTAAAGCAGCAAGAAGGAGCAAGACAGATAGCT
AGGAAAGAATGGAAGGAGATAGGAAAAATAAAGGAGATCAAGGAGGGGTATCTTA
GCCTAGTAATTCATGAAATATCTAAGATGGTTATCAAATACAACGCTATCATAGCGA
TGGAAGACTTATCTTATGGTTTCAAGAAAGGAAGGTTCAAAGTAGAGCGTCAAGTTT
ATCAAAAGTTCGAAACGATGTTGATTAATAAACTAAACTATTTGGTATTTAAAGATA
TATCTATCACCGAGAATGGTGGTCTACTAAAGGGTTACCAGCTTACATACATACCGG
ACAAACTTAAAAACGTCGGACATCAGTGTGGATGCATTTTCTACGTTCCAGCTGCAT
ATACCAGCAAGATCGACCCAACGACTGGGTTCGTAAATATTTTTAAATTCAAGGATT
TGACTGTCGACGCCAAAAGAGAGTTCATAAAAAAGTTCGATTCAATTAGGTACGAC
AGCGAAAAGAATTTGTTCTGCTTTACTTTTGACTATAACAATTTCATTACTCAGAACA
CTGTAATGTCTAAGTCCTCTTGGTCAGTCTATACTTATGGCGTTCGTATCAAACGTAG
ATTTGTTAACGGTAGATTCTCAAATGAAAGTGATACAATAGATATCACGAAAGATAT
GGAGAAAACATTAGAAATGACAGACATAAACTGGAGAGACGGACATGACTTGAGA
CAGGACATTATTGACTACGAGATCGTGCAGCACATCTTTGAGATCTTTCGTTTGACC
GTACAAATGCGTAACAGTTTATCTGAGCTTGAGGACAGGGACTACGATAGATTGAT
ATCACCTGTATTAAATGAGAATAACATCTTCTATGATTCCGCAAAAGCAGGCGACGC
TCTACCCAAAGACGCTGATGCGAACGGTGCTTATTGCATAGCTTTAAAGGGTTTGTA
TGAGATCAAACAGATAACAGAAAATTGGAAGGAAGATGGTAAGTTCTCCCGTGACA
AGCTTAAAATATCAAATAAGGACTGGTTCGATTTTATACAGAATAAGCGTTATTA
SEQ ID NO: 34
ATGAACAATGGAACTAATAACTTCCAGAATTTCATTGGTATCTCCTCTTTACAAAAA
ACTCTAAGAAACGCCCTAATTCCGACTGAAACTACACAGCAATTCATCGTCAAAAAC
GGGATCATTAAGGAGGATGAGTTGAGGGGTGAAAATCGTCAAATTCTTAAAGACAT
CATGGACGACTACTACAGGGGGTTCATCAGCGAGACGTTATCTAGTATAGACGATAT
AGACTGGACTTCACTGTTCGAGAAGATGGAAATCCAATTAAAAAATGGGGACAATA
AAGATACACTTATAAAGGAACAGACAGAGTATAGAAAGGCAATACACAAAAAGTTT
GCCAACGACGATCGTTTCAAGAACATGTTTAGTGCTAAATTGATTTCAGATATTCTG
CCGGAATTTGTTATTCACAACAATAATTATAGCGCCAGTGAGAAAGAAGAAAAAAC
GCAGGTTATCAAACTGTTCAGTCGTTTCGCTACATCTTTTAAGGATTACTTTAAAAAC
CGTGCAAATTGTTTTTCAGCCGACGATATTAGTAGCAGCTCTTGTCACCGTATTGTTA
ATGATAATGCGGAGATTTTCTTTTCAAACGCATTGGTCTACAGGAGGATAGTCAAGT
CCCTTTCAAATGACGACATTAATAAGATCTCAGGTGACATGAAAGATTCCTTAAAGG
AAATGTCCCTGGAAGAGATCTATTCCTATGAAAAGTACGGTGAGTTCATTACTCAAG
AGGGTATAAGCTTTTACAATGACATATGTGGTAAGGTTAATAGCTTTATGAACCTGT
ATTGCCAGAAGAACAAAGAAAATAAGAATCTGTATAAGTTGCAAAAGCTACACAAA
CAAATTTTGTGCATTGCCGATACATCATACGAGGTGCCATACAAATTCGAGAGCGAT
GAGGAGGTTTATCAGAGCGTGAATGGATTCCTGGACAATATTAGTAGTAAGCATATC
GTGGAAAGGCTTAGAAAGATAGGTGACAATTACAATGGCTACAATCTGGATAAAAT
CTACATCGTCTCAAAATTCTATGAAAGTGTATCCCAGAAGACGTACCGTGATTGGGA
AACTATCAACACCGCTCTGGAGATACATTACAACAATATACTTCCCGGAAACGGCA
AGTCAAAAGCCGACAAAGTCAAAAAAGCGGTCAAGAACGATTTACAAAAGTCTATC
ACTGAAATTAATGAATTAGTTAGTAATTACAAACTGTGTAGTGATGATAATATTAAG
GCAGAGACTTACATACACGAAATTTCACACATTTTAAACAACTTCGAGGCACAGGA
ACTTAAATATAATCCTGAAATTCACCTGGTTGAAAGTGAATTGAAAGCCAGCGAGCT
AAAGAACGTTTTGGACGTAATCATGAACGCATTCCACTGGTGCTCTGTCTTTATGAC
AGAGGAACTAGTGGATAAGGACAATAATTTTTATGCGGAGCTGGAGGAAATATACG
ATGAGATATATCCCGTAATATCATTATATAATCTGGTAAGAAACTATGTGACTCAAA
AGCCGTATAGCACCAAGAAAATTAAACTTAATTTCGGCATACCCACTTTAGCGGACG
GCTGGTCAAAATCCAAAGAGTATAGTAATAATGCCATCATCCTGATGCGTGACAACC
TGTACTATTTAGGTATATTTAACGCCAAAAATAAACCCGACAAAAAGATTATAGAG
GGCAACACCTCAGAGAACAAAGGTGATTATAAGAAGATGATTTACAACCTTTTACC
CGGTCCTAATAAGATGATTCCCAAAGTCTTTCTATCTAGCAAAACTGGTGTTGAAAC
ATACAAACCCTCAGCTTATATTTTAGAAGGGTATAAGCAGAATAAGCATATTAAAA
GCTCCAAAGATTTCGATATTACCTTTTGCCATGACTTGATAGACTATTTCAAAAATTG
TATTGCCATTCACCCTGAATGGAAAAACTTCGGATTTGACTTCTCTGACACATCCAC
CTACGAAGACATTTCAGGTTTTTACAGGGAAGTCGAGCTACAGGGTTATAAAATTGA
TTGGACATACATCAGCGAGAAAGATATTGACCTACTTCAAGAAAAAGGGCAGCTAT
ACCTGTTCCAGATATACAATAAAGACTTCAGTAAAAAAAGCACCGGGAACGATAAT
CTTCACACAATGTACTTAAAAAATTTATTTAGTGAAGAGAATCTGAAGGATATAGTG
CTGAAGTTAAACGGGGAGGCAGAGATATTTTTTAGAAAATCTAGTATTAAGAATCC
GATCATCCACAAGAAGGGTTCTATCCTTGTTAATAGGACTTATGAGGCAGAAGAAA
AAGACCAATTCGGCAACATACAAATTGTCCGTAAAAATATCCCTGAGAACATTTATC
AGGAACTATACAAGTACTTCAATGATAAAAGCGACAAGGAGCTGAGCGACGAGGCT
GCTAAGTTAAAGAATGTGGTGGGCCACCATGAGGCAGCAACGAATATTGTGAAGGA
CTATCGTTATACCTACGATAAATACTTTCTTCATATGCCGATCACCATTAATTTCAAG
GCAAACAAAACTGGCTTCATTAACGATCGTATCTTACAATATATCGCAAAAGAGAA
AGACCTTCACGTTATCGGGATCGATAGAGGCGAGCGTAACCTAATTTATGTTTCTGT
GATAGACACCTGTGGGAACATAGTCGAACAGAAATCATTTAATATTGTTAACGGCTA
CGATTATCAGATAAAGTTGAAGCAACAAGAGGGTGCACGTCAAATAGCAAGGAAAG
AATGGAAAGAAATAGGCAAGATTAAAGAAATAAAAGAAGGTTATTTATCCCTTGTA
ATACACGAAATTAGCAAAATGGTGATTAAATATAATGCGATCATTGCCATGGAGGA
TCTTTCTTACGGCTTCAAAAAGGGGAGATTCAAAGTCGAGAGGCAGGTGTATCAGA
AGTTTGAGACCATGCTAATCAATAAACTAAATTATCTAGTATTCAAAGACATAAGCA
TCACCGAAAATGGCGGCTTGTTGAAGGGTTATCAATTGACCTACATCCCAGATAAAC
TAAAAAACGTAGGGCATCAATGCGGATGTATATTTTACGTTCCAGCCGCATACACTT
CCAAAATCGATCCAACTACGGGTTTTGTGAACATCTTCAAATTCAAAGACTTGACTG
TCGATGCTAAGAGGGAGTTTATCAAGAAATTTGACTCCATTAGATACGACAGTGAG
AAGAATCTGTTCTGTTTTACCTTTGATTATAACAACTTTATAACTCAAAACACAGTCA
TGAGTAAGTCATCTTGGTCAGTGTATACGTATGGTGTGAGGATTAAAAGGAGGTTTG
TTAACGGGAGATTTTCCAATGAAAGTGATACAATAGATATAACCAAGGACATGGAA
AAGACTCTTGAAATGACCGACATTAACTGGAGAGATGGCCACGACTTACGTCAAGA
TATAATCGATTACGAGATAGTGCAACATATCTTTGAGATATTTAGGCTTACTGTCCA
AATGCGTAACTCATTAAGTGAGTTGGAGGACAGGGATTACGATAGGCTAATAAGTC
CTGTTCTTAACGAAAACAATATATTCTACGATTCAGCAAAGGCGGGAGACGCCCTGC
CCAAGGACGCGGATGCTAACGGCGCATACTGTATTGCCCTGAAAGGCTTGTACGAG
ATAAAACAGATCACGGAGAACTGGAAAGAAGATGGAAAATTCAGTCGTGACAAGTT
AAAAATTAGTAACAAAGACTGGTTCGACTTTATTCAGAACAAGAGATATCTG
SEQ ID NO: 35
ATGAACAACGGAACCAATAACTTTCAAAACTTTATAGGCATCTCCAGTCTACAGAAG
ACACTACGTAACGCTTTGATACCAACTGAGACCACGCAGCAGTTTATCGTCAAGAAC
GGTATTATAAAGGAAGACGAGCTAAGGGGGGAAAACCGTCAGATCTTAAAGGACAT
CATGGATGACTACTACAGAGGCTTCATAAGTGAGACTTTGTCTAGTATAGACGACAT
CGACTGGACCAGTTTATTTGAGAAGATGGAAATTCAGTTAAAGAACGGGGACAATA
AAGACACACTAATTAAAGAGCAGACCGAATACAGAAAAGCTATACACAAAAAGTTT
GCCAACGATGATAGATTCAAAAATATGTTTTCAGCAAAATTGATTTCCGACATATTG
CCAGAATTCGTAATCCATAATAACAATTATTCTGCAAGTGAGAAGGAAGAGAAGAC
CCAAGTAATCAAGCTGTTTTCCCGTTTTGCTACGAGTTTCAAAGATTATTTCAAGAAT
AGGGCTAATTGTTTCTCCGCGGACGACATAAGTAGCAGTTCCTGTCACAGGATTGTG
AACGATAATGCTGAGATATTTTTTTCCAATGCCCTAGTGTATAGGAGAATAGTTAAA
AGCTTAAGCAACGACGATATCAATAAAATTTCAGGGGACATGAAGGACAGCTTAAA
GGAAATGAGTTTGGAGGAGATTTACAGTTATGAAAAATACGGAGAGTTTATAACTC
AGGAAGGCATCTCTTTCTATAATGATATCTGTGGGAAGGTAAACTCCTTCATGAATT
TATATTGCCAGAAGAATAAGGAAAACAAAAATCTTTACAAGCTTCAAAAGTTACAT
AAGCAGATCTTATGTATTGCCGACACGAGTTATGAAGTGCCTTATAAATTCGAGAGT
GATGAGGAAGTGTATCAGTCTGTTAACGGATTCCTAGATAATATAAGTTCCAAACAT
ATAGTCGAGAGGCTGAGGAAGATTGGCGATAACTATAATGGATATAATCTTGACAA
AATCTATATAGTCTCTAAATTTTATGAAAGCGTCAGCCAGAAGACATATAGAGATTG
GGAAACTATAAACACAGCCCTTGAAATACATTACAATAACATCCTACCCGGCAATG
GTAAGTCTAAGGCAGACAAAGTTAAAAAAGCAGTAAAGAATGACTTACAGAAGTCA
ATCACGGAGATAAATGAGTTGGTCAGTAACTACAAATTATGCTCCGACGATAATATT
AAGGCCGAAACATATATACACGAGATAAGTCATATATTAAACAATTTCGAAGCCCA
GGAGTTAAAATATAACCCTGAAATTCATCTGGTCGAAAGTGAGTTAAAGGCCAGTG
AGTTAAAGAATGTACTTGACGTAATTATGAATGCTTTTCATTGGTGCTCCGTGTTCAT
GACCGAGGAGTTAGTAGATAAAGACAATAACTTTTACGCCGAACTTGAAGAGATAT
ACGACGAGATTTATCCGGTAATCAGCTTGTACAACTTAGTTAGAAATTATGTAACAC
AGAAGCCTTACTCTACTAAAAAAATAAAACTGAACTTTGGTATCCCAACTCTTGCAG
ATGGTTGGAGTAAAAGCAAGGAATATAGCAACAATGCGATCATCTTGATGAGAGAC
AACTTGTACTATTTGGGAATCTTCAACGCGAAAAATAAACCCGACAAAAAAATCAT
CGAAGGGAATACCTCTGAGAATAAAGGTGACTATAAGAAAATGATTTACAATCTAC
TTCCTGGTCCTAATAAAATGATCCCGAAAGTGTTTCTTAGTTCTAAGACTGGTGTCG
AGACGTACAAACCTAGCGCGTACATCTTAGAAGGGTACAAGCAGAATAAACACATC
AAATCAAGCAAAGACTTCGATATTACTTTTTGCCATGACTTGATAGACTACTTTAAA
AACTGCATAGCAATCCACCCGGAGTGGAAAAACTTTGGCTTTGATTTCTCTGACACC
TCTACATATGAGGACATATCTGGTTTTTACCGTGAGGTTGAATTGCAGGGATACAAA
ATTGACTGGACTTACATATCTGAAAAAGATATCGATCTATTGCAGGAGAAAGGCCA
GCTTTACCTTTTCCAGATCTATAATAAGGACTTCTCTAAGAAGTCTACAGGGAATGA
TAATTTGCACACTATGTACTTAAAAAATCTGTTTTCCGAGGAAAACTTGAAAGACAT
TGTTTTAAAGTTGAACGGAGAAGCTGAAATATTTTTCAGAAAGAGCTCCATAAAAA
ACCCGATCATTCATAAGAAGGGATCTATCCTGGTTAACAGAACGTACGAAGCGGAA
GAAAAAGACCAATTCGGAAACATTCAAATTGTTAGAAAGAATATCCCTGAGAACAT
CTACCAGGAGTTATATAAGTATTTTAATGATAAGTCAGATAAGGAACTATCTGACGA
AGCGGCGAAGCTTAAAAATGTTGTAGGACACCATGAGGCTGCTACAAATATAGTCA
AGGACTACCGTTATACCTACGATAAGTACTTTCTACACATGCCCATTACCATCAATTT
TAAAGCTAATAAAACGGGTTTTATCAACGATCGTATCCTACAATATATTGCGAAAGA
GAAGGATTTGCATGTCATTGGCATTGATAGAGGTGAGAGGAACCTAATATACGTATC
CGTGATTGATACGTGCGGGAACATAGTTGAACAGAAATCATTTAATATAGTTAATGG
GTACGACTATCAGATTAAGCTAAAGCAACAAGAAGGCGCCAGGCAAATTGCCCGTA
AAGAATGGAAAGAGATCGGGAAGATCAAGGAAATAAAAGAAGGATACCTTTCCCT
GGTCATCCATGAAATTAGCAAAATGGTGATTAAGTACAATGCCATAATCGCGATGG
AGGACTTAAGCTACGGGTTCAAAAAGGGGAGGTTTAAGGTGGAGAGGCAAGTGTAC
CAGAAATTTGAGACCATGCTAATCAACAAACTGAACTACCTAGTTTTTAAGGACATT
TCAATTACAGAGAATGGAGGACTTTTAAAGGGTTACCAACTAACGTATATACCAGAT
AAGTTGAAAAATGTCGGTCACCAGTGTGGCTGCATCTTTTACGTTCCCGCCGCTTAT
ACATCTAAAATTGATCCAACCACAGGCTTTGTAAATATCTTTAAATTCAAAGATTTA
ACTGTGGATGCAAAAAGAGAGTTTATCAAGAAATTCGATAGCATTCGTTATGATAGC
GAGAAGAACCTGTTCTGCTTTACTTTCGACTATAACAACTTTATAACTCAAAACACC
GTGATGTCAAAAAGCTCATGGTCAGTCTACACCTATGGTGTAAGGATTAAAAGGCGT
TTCGTGAATGGGAGATTCTCCAATGAAAGTGACACGATCGACATAACAAAGGACAT
GGAGAAGACACTAGAGATGACTGATATTAATTGGAGAGACGGACACGATCTGCGTC
AAGATATAATTGATTATGAGATAGTACAGCACATATTTGAGATCTTCCGTTTGACTG
TCCAAATGCGTAATTCCCTTTCTGAGCTGGAAGATAGGGACTATGATAGATTAATAT
CCCCTGTACTAAATGAGAACAACATTTTCTATGATAGTGCAAAAGCCGGGGATGCAT
TGCCGAAAGACGCTGACGCTAATGGGGCGTACTGTATAGCTTTAAAGGGGCTTTACG
AAATAAAGCAGATAACCGAAAACTGGAAGGAAGATGGCAAATTCTCAAGGGACAA
ACTTAAGATCTCTAACAAGGATTGGTTCGATTTTATACAAAACAAACGTTATTTG
SEQ ID NO: 36
ATGAATAATGGTACAAACAACTTTCAGAATTTCATTGGGATCTCTAGCTTACAGAAG
ACCCTGAGGAATGCGTTGATTCCAACTGAAACAACCCAGCAATTCATCGTGAAAAA
TGGGATAATCAAAGAGGATGAGTTAAGGGGTGAAAACCGTCAAATATTGAAGGATA
TTATGGACGACTACTACCGTGGATTCATCTCAGAGACGTTGAGCAGCATTGACGACA
TAGACTGGACTAGCCTTTTCGAGAAGATGGAAATTCAGTTAAAGAACGGAGATAAC
AAAGATACACTAATCAAGGAACAGACAGAATACAGAAAAGCAATTCATAAGAAATT
CGCTAATGACGATCGTTTTAAAAACATGTTCTCTGCAAAATTAATTAGCGACATTCT
GCCGGAATTCGTTATACATAATAATAACTACAGTGCTTCTGAAAAGGAAGAGAAAA
CTCAGGTAATAAAACTGTTCTCTCGTTTTGCCACATCCTTCAAAGACTACTTTAAAAA
TAGAGCGAACTGCTTTAGCGCCGACGATATTAGTTCTTCCTCATGCCACAGGATTGT
CAACGATAATGCAGAGATATTCTTTTCTAACGCACTAGTCTACAGAAGGATTGTAAA
GTCTTTGTCAAATGATGACATAAACAAGATTAGTGGAGATATGAAAGACTCTCTAAA
GGAAATGAGCCTTGAGGAGATATACTCTTATGAAAAGTACGGTGAGTTTATTACCCA
AGAAGGCATTAGTTTCTATAATGACATTTGTGGAAAAGTTAACAGTTTTATGAATCT
ATACTGTCAAAAAAATAAGGAGAATAAAAATCTTTATAAGTTGCAAAAACTGCATA
AGCAGATATTATGTATAGCAGACACGAGCTATGAGGTACCGTACAAGTTCGAGAGC
GATGAGGAAGTCTACCAATCTGTCAACGGATTTTTGGACAACATTTCTTCAAAACAT
ATTGTGGAGAGGCTTAGGAAAATAGGCGACAATTATAATGGATATAACTTAGATAA
GATATATATTGTTTCCAAATTCTACGAATCTGTAAGCCAGAAGACATACAGAGATTG
GGAAACGATAAACACAGCCCTTGAAATTCACTATAACAACATACTACCTGGAAACG
GCAAATCAAAGGCCGACAAAGTTAAGAAGGCCGTAAAGAATGATTTACAGAAGAG
CATAACGGAGATCAATGAGCTGGTGTCTAACTATAAATTGTGTAGCGATGACAACAT
AAAAGCCGAGACTTACATTCACGAAATTTCACACATACTTAACAACTTTGAAGCTCA
GGAATTAAAGTATAATCCCGAAATACACCTTGTGGAGTCCGAACTAAAGGCTAGTG
AGCTTAAGAACGTCCTAGACGTAATTATGAATGCCTTCCACTGGTGTAGTGTTTTTAT
GACCGAGGAACTTGTTGACAAAGATAATAATTTTTATGCAGAACTAGAAGAGATAT
ACGATGAAATATACCCGGTGATCAGTTTGTACAATCTTGTCAGGAACTATGTGACAC
AAAAGCCCTATTCAACAAAGAAAATAAAACTTAATTTCGGAATTCCTACGTTAGCTG
ATGGCTGGTCTAAATCCAAGGAATACAGCAACAACGCTATAATTCTGATGAGAGAT
AACTTGTACTATCTAGGCATCTTCAATGCCAAAAATAAGCCTGATAAGAAGATTATA
GAGGGCAACACTTCAGAGAACAAGGGCGACTACAAGAAAATGATCTATAACCTATT
GCCTGGCCCAAACAAGATGATTCCGAAGGTCTTCCTATCATCCAAGACCGGCGTTGA
GACATACAAGCCATCAGCGTATATTTTAGAGGGGTACAAACAAAACAAGCACATAA
AGTCTAGTAAAGACTTCGATATAACATTTTGTCATGACTTAATTGACTACTTTAAGA
ATTGCATCGCTATACACCCGGAATGGAAGAATTTCGGCTTCGACTTCTCTGATACAT
CTACCTACGAGGACATTAGCGGGTTTTACCGTGAAGTCGAATTACAAGGGTATAAG
ATAGATTGGACGTACATCTCTGAGAAAGACATAGACTTGCTTCAGGAAAAGGGCCA
GTTGTATCTATTCCAAATATACAATAAGGATTTTTCCAAGAAATCTACGGGTAATGA
CAATCTTCACACAATGTATCTTAAGAACCTTTTCTCAGAAGAGAACCTGAAGGACAT
TGTCTTAAAACTAAATGGCGAAGCTGAGATTTTTTTCAGGAAGTCTTCAATTAAGAA
CCCGATAATCCACAAGAAGGGGAGTATTCTTGTGAATAGAACTTACGAGGCCGAAG
AAAAAGACCAATTTGGTAACATCCAGATAGTCAGAAAGAACATTCCAGAGAACATC
TACCAAGAGCTATACAAATATTTCAACGACAAGTCCGATAAGGAACTGTCCGATGA
GGCAGCCAAGTTGAAGAATGTCGTGGGTCATCATGAAGCTGCTACTAACATTGTCAA
GGACTATCGTTATACTTACGACAAGTATTTCCTACACATGCCGATAACAATTAATTT
CAAGGCTAACAAAACAGGCTTTATCAACGATCGTATCTTGCAGTACATAGCTAAGG
AAAAGGATTTGCATGTGATTGGCATTGATAGAGGGGAGCGTAACTTGATATATGTGT
CTGTCATAGACACGTGTGGCAACATCGTCGAACAGAAATCATTCAACATAGTAAAC
GGCTACGATTACCAAATTAAGCTGAAACAGCAAGAGGGTGCACGTCAAATTGCGCG
TAAAGAGTGGAAAGAAATTGGTAAAATCAAGGAAATTAAAGAAGGCTACTTGTCTC
TTGTTATACATGAAATTTCCAAGATGGTTATAAAGTATAACGCGATAATTGCTATGG
AAGACTTATCATACGGGTTTAAAAAGGGGAGGTTCAAGGTAGAGAGGCAGGTCTAT
CAAAAGTTCGAGACGATGTTGATTAATAAACTAAACTATCTAGTGTTCAAAGATATC
AGCATTACGGAGAACGGGGGGCTACTGAAAGGATATCAACTAACGTACATTCCCGA
TAAGTTAAAGAACGTTGGTCATCAATGTGGTTGCATCTTCTACGTGCCTGCTGCCTAT
ACGTCCAAAATAGATCCAACTACTGGATTTGTTAACATCTTTAAATTCAAAGATTTA
ACCGTAGACGCCAAAAGGGAATTTATAAAAAAATTTGACAGCATCCGTTACGATAG
CGAAAAGAATCTGTTCTGTTTTACTTTCGACTACAATAATTTCATCACGCAAAATAC
GGTAATGTCTAAGTCAAGTTGGAGCGTCTACACGTATGGAGTCAGGATCAAGAGGC
GTTTCGTAAATGGAAGATTCTCTAATGAGTCAGATACTATAGACATCACGAAAGATA
TGGAGAAAACCTTGGAGATGACGGATATTAACTGGCGTGATGGACACGATTTAAGA
CAGGACATTATTGACTATGAGATTGTGCAACACATCTTCGAAATATTCCGTCTAACA
GTCCAAATGAGGAATAGCCTAAGTGAATTGGAGGACCGTGATTACGATAGGCTTAT
AAGTCCTGTCCTTAACGAAAACAATATTTTCTATGATAGTGCTAAGGCGGGGGACGC
ACTGCCTAAAGACGCAGATGCTAACGGGGCATACTGCATTGCGTTAAAGGGTCTGT
ACGAAATCAAGCAGATTACGGAAAACTGGAAAGAGGATGGCAAGTTTAGCAGAGA
TAAGTTGAAGATAAGTAACAAAGATTGGTTTGACTTTATTCAGAATAAAAGGTATTT
A
SEQ ID NO: 37
ATGAATAACGGCACTAATAATTTCCAGAATTTCATCGGCATTAGCAGCTTACAAAAG
ACGTTGAGGAATGCCTTAATACCCACAGAAACTACTCAACAATTTATAGTGAAGAAT
GGGATAATTAAGGAAGACGAGTTGAGAGGTGAAAATAGGCAAATCTTGAAAGACAT
TATGGATGACTACTACAGGGGCTTCATTAGTGAAACGTTGTCTTCAATAGATGACAT
TGATTGGACTTCTTTGTTTGAGAAGATGGAAATACAGTTAAAGAACGGCGACAATA
AGGATACACTTATCAAAGAGCAAACAGAATATAGAAAAGCAATTCACAAAAAGTTT
GCTAACGATGATAGGTTCAAGAACATGTTTAGCGCTAAACTAATATCAGACATCCTT
CCCGAGTTCGTTATTCATAACAATAACTATAGTGCAAGTGAAAAAGAGGAGAAGAC
ACAGGTGATTAAGCTGTTCTCCAGATTCGCGACTTCTTTCAAAGATTACTTCAAAAA
CAGAGCCAACTGTTTTTCAGCTGACGATATCTCTAGTAGTAGTTGTCACCGTATAGT
GAACGATAACGCTGAGATCTTCTTTAGCAATGCATTAGTGTATAGAAGGATAGTTAA
GTCTCTAAGCAATGATGATATCAATAAAATTTCCGGAGACATGAAGGACTCCCTAAA
GGAAATGTCCTTAGAAGAGATCTACTCATATGAGAAATACGGGGAATTTATTACGC
AGGAAGGGATCTCCTTTTACAATGACATATGCGGGAAGGTCAACTCTTTCATGAACT
TATACTGCCAAAAGAACAAGGAGAACAAGAATTTATATAAACTTCAGAAACTTCAC
AAACAAATACTGTGCATAGCCGATACCTCATATGAGGTTCCTTACAAATTTGAATCA
GATGAAGAGGTATACCAATCCGTTAACGGCTTTCTTGACAATATTAGCTCAAAGCAC
ATCGTGGAGAGGTTGAGAAAGATTGGTGATAATTATAATGGCTACAATCTAGATAA
GATATATATTGTTAGCAAGTTCTACGAGTCTGTGTCCCAAAAAACATATAGGGATTG
GGAGACAATTAATACTGCTCTAGAAATCCATTACAACAACATCCTTCCTGGAAATGG
CAAGAGTAAGGCCGACAAAGTCAAGAAAGCAGTGAAAAATGATCTGCAAAAATCA
ATTACTGAGATAAACGAGCTAGTATCTAATTACAAGCTTTGTAGCGACGATAACATT
AAGGCAGAAACGTACATACACGAGATTAGTCACATCTTAAATAATTTTGAAGCCCA
AGAACTGAAATATAACCCTGAGATACACCTTGTTGAATCCGAGTTAAAGGCGTCTGA
ACTAAAAAACGTGTTAGACGTTATTATGAATGCCTTCCACTGGTGTAGCGTCTTTAT
GACTGAGGAGTTGGTTGATAAGGATAATAACTTTTACGCTGAATTGGAAGAAATTTA
TGACGAAATCTATCCTGTTATTTCTCTATATAATTTGGTGAGAAATTACGTAACGCA
AAAGCCCTATAGTACGAAAAAAATAAAACTAAATTTCGGGATCCCTACCCTAGCCG
ACGGTTGGTCTAAATCCAAGGAGTACTCAAACAATGCAATAATATTGATGAGGGAC
AACCTGTACTACCTAGGCATATTTAATGCCAAAAATAAGCCCGATAAAAAGATTATA
GAAGGGAACACGTCAGAAAATAAAGGAGACTATAAGAAAATGATCTACAACCTTTT
GCCCGGCCCCAATAAAATGATCCCGAAGGTCTTCCTAAGTAGCAAGACTGGCGTAG
AGACCTACAAACCATCTGCATACATTTTGGAGGGGTACAAGCAAAACAAGCACATA
AAGAGTAGTAAGGATTTTGACATTACATTCTGCCATGACTTAATTGACTACTTTAAA
AATTGCATCGCAATTCACCCTGAATGGAAAAATTTTGGATTTGATTTCTCTGATACTT
CAACATATGAGGATATTTCAGGGTTCTACAGGGAGGTCGAACTACAGGGTTACAAA
ATAGACTGGACGTATATTTCTGAGAAAGATATAGATTTGCTTCAGGAAAAGGGTCA
GCTATATCTGTTCCAGATATATAATAAGGACTTCTCCAAAAAGAGTACCGGAAATGA
TAATCTGCACACAATGTACTTAAAAAACTTGTTCTCTGAGGAGAATCTAAAAGACAT
CGTACTAAAACTTAACGGGGAGGCCGAAATTTTTTTTAGGAAGTCCAGCATCAAGA
ACCCGATTATTCATAAAAAAGGTAGCATTTTGGTGAACCGTACTTATGAGGCGGAAG
AAAAAGACCAATTCGGTAATATTCAAATCGTTAGAAAGAACATCCCTGAGAACATT
TATCAGGAACTATACAAATACTTTAACGACAAATCAGATAAGGAGCTTTCTGATGAG
GCAGCTAAATTGAAAAATGTAGTGGGACATCACGAAGCAGCCACTAACATAGTGAA
GGACTACAGATACACATACGATAAGTACTTCCTGCACATGCCTATTACAATTAACTT
TAAAGCAAATAAAACAGGGTTTATTAACGACAGAATCTTACAGTATATTGCCAAAG
AAAAGGATCTGCATGTGATAGGAATAGACAGAGGAGAAAGAAACCTGATATACGTC
TCCGTGATTGATACATGTGGGAACATAGTAGAACAGAAGTCCTTTAACATTGTTAAT
GGGTACGATTATCAAATTAAATTAAAACAACAAGAAGGAGCACGTCAAATAGCTAG
GAAAGAATGGAAAGAGATAGGAAAAATTAAGGAAATTAAGGAGGGTTACCTGTCC
CTTGTAATTCATGAAATATCCAAAATGGTAATTAAATATAACGCGATCATCGCGATG
GAAGATCTAAGCTACGGGTTCAAAAAAGGCAGGTTTAAGGTGGAGAGGCAAGTTTA
CCAAAAGTTCGAGACAATGTTGATTAATAAGTTAAACTACTTAGTTTTCAAAGATAT
CTCCATAACCGAGAATGGCGGGCTTTTAAAAGGGTACCAACTAACATATATCCCGG
ATAAATTGAAGAACGTTGGACACCAGTGTGGCTGCATATTTTATGTACCCGCTGCGT
ATACTTCTAAAATTGACCCGACCACCGGGTTTGTAAACATATTCAAGTTTAAGGACC
TAACAGTTGACGCCAAACGTGAGTTCATCAAGAAGTTCGATAGTATAAGGTATGACT
CTGAGAAGAACCTTTTCTGCTTCACGTTTGACTATAATAATTTCATCACCCAAAATAC
AGTTATGTCAAAAAGCTCTTGGTCAGTATATACGTATGGCGTAAGGATTAAGCGTAG
GTTCGTGAACGGTAGATTTTCCAACGAGTCAGATACTATTGATATTACCAAGGATAT
GGAGAAGACATTAGAAATGACAGATATAAATTGGAGGGATGGGCACGATCTAAGGC
AAGATATCATTGATTACGAAATTGTTCAGCACATATTCGAGATATTCCGTCTTACAG
TACAAATGCGTAACAGCTTGTCTGAGTTGGAAGATCGTGACTATGACAGGTTGATAT
CACCGGTCTTGAACGAGAACAATATATTCTACGACAGCGCTAAGGCGGGAGACGCT
CTGCCTAAAGACGCAGATGCCAATGGGGCGTACTGCATTGCCTTAAAAGGCTTATAC
GAGATTAAACAGATCACAGAGAACTGGAAAGAGGACGGCAAGTTTTCTAGAGATAA
ATTGAAAATCTCAAACAAAGACTGGTTCGATTTCATCCAAAACAAAAGATACCTT
SEQ ID NO: 38
ATGAACAATGGAACTAACAACTTCCAGAACTTTATCGGCATCTCTTCCCTCCAAAAG
ACACTGAGAAATGCACTGATCCCAACCGAAACGACTCAACAATTTATTGTTAAGAA
CGGCATCATAAAAGAAGACGAGCTTCGCGGCGAGAACCGCCAGATACTTAAGGATA
TTATGGACGATTATTACCGAGGCTTTATCAGCGAAACTCTTAGCTCTATTGATGATAT
CGACTGGACCTCCCTCTTCGAAAAAATGGAGATACAGCTCAAGAACGGCGATAATA
AAGACACCTTGATAAAGGAACAGACTGAGTACAGGAAAGCGATCCACAAGAAATTC
GCGAACGACGACAGGTTTAAAAACATGTTCTCTGCAAAATTGATATCCGACATCTTG
CCGGAATTTGTGATACACAACAATAACTATAGCGCTTCAGAGAAAGAAGAGAAGAC
CCAAGTAATCAAGTTGTTCAGCCGCTTCGCAACGTCTTTTAAAGATTACTTTAAGAA
CCGGGCCAATTGTTTCTCCGCGGATGATATTAGCTCATCAAGTTGCCATCGAATTGT
CAATGATAATGCGGAGATCTTCTTCAGCAATGCGCTGGTCTACAGACGAATCGTAAA
AAGTCTTTCAAATGACGACATCAATAAGATTAGTGGAGATATGAAGGATTCCCTTAA
GGAAATGAGTCTTGAAGAAATATACTCATACGAAAAGTACGGGGAATTTATTACCC
AGGAGGGGATCTCCTTCTATAACGACATCTGTGGAAAAGTAAACTCATTCATGAACC
TGTACTGTCAGAAAAACAAAGAAAACAAAAATCTGTATAAACTCCAAAAATTGCAC
AAGCAAATATTGTGTATAGCGGACACATCATACGAGGTTCCATATAAGTTCGAAAGT
GATGAAGAAGTCTACCAATCAGTGAATGGGTTTCTGGACAACATTAGTTCCAAGCAC
ATAGTTGAACGACTGCGAAAGATTGGTGACAATTACAACGGCTATAATTTGGACAA
GATTTATATAGTTAGCAAATTTTATGAATCCGTATCACAAAAGACTTATAGAGACTG
GGAAACAATCAACACGGCACTTGAGATCCATTATAACAATATTCTTCCAGGGAACG
GCAAAAGCAAGGCTGATAAGGTAAAAAAGGCCGTTAAGAATGATCTTCAAAAATCC
ATAACGGAGATCAACGAACTTGTAAGTAACTACAAATTGTGCTCTGACGACAATAT
AAAGGCTGAAACGTATATTCACGAGATTAGCCATATCCTGAATAACTTTGAGGCCCA
AGAACTCAAGTATAACCCGGAAATACATTTGGTAGAAAGCGAGCTTAAAGCGAGTG
AGCTGAAAAACGTCCTCGATGTGATCATGAATGCTTTCCACTGGTGTAGTGTCTTTA
TGACTGAGGAGTTGGTTGATAAAGACAATAATTTCTACGCTGAACTGGAAGAAATTT
ACGACGAAATCTATCCAGTGATCTCCCTCTATAACCTCGTTCGAAACTACGTGACGC
AGAAACCTTATTCTACAAAGAAAATTAAGTTGAACTTCGGCATTCCTACACTTGCTG
ACGGATGGTCCAAATCCAAAGAGTACTCAAACAACGCAATCATCCTCATGCGGGAT
AACCTTTATTATTTGGGCATTTTCAACGCCAAAAACAAACCTGATAAAAAGATAATT
GAAGGCAATACGAGTGAGAACAAGGGCGACTACAAAAAAATGATATATAACTTGTT
GCCAGGCCCCAACAAGATGATTCCTAAAGTTTTTCTGTCTTCTAAGACTGGAGTTGA
AACTTACAAACCCTCCGCCTACATTCTTGAAGGGTATAAACAGAATAAGCACATAA
AGTCCTCAAAGGATTTCGACATTACGTTTTGCCATGACCTCATCGACTATTTCAAGA
ACTGTATCGCCATACATCCGGAGTGGAAGAATTTTGGATTTGATTTCTCCGACACAT
CTACCTATGAAGACATAAGCGGTTTCTACCGGGAGGTCGAGCTTCAGGGCTATAAG
ATAGATTGGACATACATTAGTGAAAAAGATATCGATCTTCTGCAAGAAAAGGGACA
ACTTTACCTTTTTCAGATTTATAATAAAGACTTTTCAAAAAAGTCCACAGGGAACGA
TAATCTGCACACCATGTATCTCAAGAATCTGTTTAGTGAAGAAAACCTTAAAGACAT
AGTTTTGAAGCTTAACGGAGAGGCTGAGATTTTTTTTAGAAAGTCCTCAATTAAAAA
CCCTATAATACACAAGAAAGGCTCTATTCTTGTTAACAGGACATATGAAGCCGAGG
AGAAAGATCAGTTTGGCAATATCCAGATTGTTCGCAAGAATATCCCGGAAAATATAT
ATCAGGAGCTGTATAAATACTTTAACGACAAGAGCGACAAGGAGCTGAGTGACGAG
GCCGCGAAGCTTAAGAATGTAGTAGGTCACCACGAAGCAGCCACCAATATCGTCAA
AGACTATAGGTACACGTACGACAAGTACTTTTTGCACATGCCTATAACTATAAACTT
CAAAGCTAATAAAACTGGGTTTATTAATGACAGGATTCTCCAATACATCGCTAAAGA
GAAGGATCTGCATGTAATTGGCATAGACAGAGGTGAGAGAAACTTGATATATGTCA
GCGTAATAGACACATGTGGCAATATCGTGGAACAGAAGTCTTTTAACATCGTCAATG
GTTACGACTACCAAATTAAGTTGAAACAGCAGGAAGGCGCACGACAGATCGCACGA
AAGGAATGGAAAGAGATAGGCAAAATAAAAGAAATAAAGGAGGGCTATCTCAGTC
TCGTTATACACGAAATTTCAAAAATGGTTATTAAGTACAATGCAATCATAGCGATGG
AGGATCTCAGTTATGGGTTCAAAAAGGGTCGGTTTAAAGTTGAGCGCCAAGTGTACC
AAAAGTTCGAGACAATGCTGATTAACAAGCTGAACTACCTCGTCTTCAAAGATATAA
GTATTACGGAGAACGGTGGCCTTCTTAAAGGCTATCAACTTACTTACATCCCGGACA
AGCTCAAAAACGTAGGGCACCAATGCGGGTGTATTTTCTATGTGCCTGCGGCATATA
CGTCAAAGATTGACCCAACCACAGGATTCGTAAACATATTCAAGTTTAAGGACCTCA
CCGTTGATGCGAAAAGGGAGTTCATTAAAAAATTTGATTCTATTCGATATGATAGTG
AGAAAAATCTCTTTTGTTTCACATTTGACTATAATAATTTTATTACTCAGAATACTGT
CATGAGCAAGTCATCTTGGTCAGTGTACACATACGGGGTGCGGATCAAACGCAGGT
TCGTCAATGGTCGCTTCTCAAACGAATCAGACACCATTGACATCACAAAGGACATGG
AAAAAACCCTTGAGATGACCGACATTAATTGGCGCGATGGTCATGATCTGCGGCAA
GACATCATAGACTACGAAATCGTCCAACACATCTTTGAGATCTTTCGCTTGACGGTC
CAAATGCGGAACTCCCTGTCCGAGCTCGAGGATAGAGATTATGATCGGCTGATATCT
CCCGTGCTTAATGAAAATAACATCTTCTACGACTCCGCCAAGGCGGGTGATGCCCTG
CCGAAGGATGCGGATGCTAATGGCGCTTATTGCATTGCTCTTAAGGGGCTCTATGAG
ATAAAGCAGATCACGGAAAACTGGAAAGAAGACGGTAAGTTTAGTAGAGACAAGC
TGAAGATCTCAAATAAAGACTGGTTTGATTTCATACAG. AAC. AAG. CGG. TAC. CTG
SEQ ID NO: 39
ATGAACAATGGCACTAACAATTTTCAGAATTTCATCGGCATTTCAAGTCTGCAAAAA
ACTCTGAGGAATGCTTTGATCCCTACTGAAACCACTCAGCAATTTATAGTCAAGAAC
GGTATAATTAAAGAAGATGAACTCAGGGGTGAAAATAGACAAATACTCAAGGACAT
TATGGATGACTATTATAGAGGCTTCATCTCAGAGACTCTCTCATCAATAGATGATAT
CGATTGGACTAGCCTTTTCGAGAAAATGGAGATTCAGTTGAAAAATGGTGATAACA
AAGATACGTTGATAAAGGAACAGACCGAGTACAGGAAAGCCATTCATAAGAAATTT
GCTAATGACGATAGATTTAAGAATATGTTTAGTGCAAAACTGATTAGTGACATTCTG
CCGGAGTTCGTTATCCATAATAATAACTACTCTGCATCCGAAAAGGAGGAAAAGAC
GCAAGTTATTAAACTGTTCAGCCGCTTCGCCACAAGCTTCAAGGACTACTTCAAAAA
TAGAGCCAACTGCTTTTCTGCCGACGATATATCATCATCTTCATGCCATCGGATCGTT
AACGATAACGCCGAGATATTCTTCAGCAACGCCCTTGTATATCGAAGAATAGTCAAA
AGTCTGAGTAATGATGATATTAATAAAATTAGCGGTGATATGAAAGACTCCCTGAA
GGAAATGTCACTGGAGGAAATTTATAGTTACGAAAAGTACGGCGAATTCATTACTC
AAGAAGGCATATCCTTCTATAACGACATTTGCGGAAAGGTCAACTCATTCATGAACC
TTTATTGCCAGAAGAATAAGGAGAATAAAAATCTTTACAAATTGCAAAAACTTCAC
AAACAAATTCTTTGCATCGCGGATACGTCCTACGAAGTTCCTTACAAATTTGAATCC
GATGAGGAAGTGTATCAGAGTGTCAATGGATTTTTGGATAATATCTCTTCAAAACAT
ATTGTGGAGAGATTGCGCAAAATAGGTGATAACTACAATGGCTACAACCTGGACAA
GATTTATATTGTTAGCAAGTTCTATGAAAGTGTCAGTCAAAAGACCTACAGAGATTG
GGAGACAATCAACACGGCGCTCGAAATACACTACAATAACATCCTCCCCGGCAATG
GGAAGAGTAAAGCCGATAAGGTTAAAAAAGCTGTTAAGAACGACCTCCAGAAATCC
ATCACGGAAATAAACGAGCTGGTTTCCAACTATAAGCTGTGTAGCGATGATAATATT
AAGGCTGAGACATATATACATGAGATCAGCCACATTCTCAACAATTTCGAGGCACA
GGAACTCAAATACAATCCCGAGATTCACTTGGTGGAAAGTGAGTTGAAGGCGTCAG
AGCTTAAGAATGTACTTGACGTAATAATGAATGCTTTTCATTGGTGCTCCGTGTTCAT
GACTGAGGAACTCGTGGATAAGGATAATAACTTTTATGCGGAGTTGGAAGAGATAT
ACGATGAAATATACCCGGTTATCTCACTGTATAATCTGGTCAGAAATTACGTGACCC
AAAAGCCTTATAGTACAAAAAAAATAAAGTTGAACTTCGGTATTCCGACATTGGCA
GATGGTTGGTCCAAAAGCAAAGAATACTCTAATAACGCCATTATATTGATGCGAGA
CAATTTGTATTACCTTGGGATCTTTAACGCGAAAAACAAACCGGATAAGAAGATCAT
CGAAGGTAATACATCTGAGAATAAGGGGGATTACAAGAAGATGATTTATAATCTGT
TGCCGGGGCCAAACAAGATGATTCCGAAGGTCTTTCTGTCATCTAAGACAGGAGTA
GAGACCTACAAACCTTCTGCGTACATTTTGGAAGGCTACAAACAGAACAAGCATAT
AAAATCTAGCAAGGACTTTGATATCACGTTTTGTCATGATCTGATAGATTATTTCAA
AAACTGCATCGCTATACATCCTGAGTGGAAGAATTTCGGCTTTGACTTTTCTGACAC
CAGCACATACGAAGACATCTCAGGTTTCTACCGGGAAGTCGAGCTCCAGGGGTACA
AGATTGACTGGACATATATAAGTGAAAAAGACATCGACCTCCTCCAAGAGAAGGGC
CAACTTTACCTGTTCCAGATCTATAACAAAGACTTTTCTAAAAAGTCCACGGGTAAC
GACAACTTGCACACTATGTATCTGAAAAACTTGTTCTCTGAAGAGAACCTCAAGGAC
ATCGTCCTGAAGCTTAACGGGGAGGCGGAGATCTTCTTTAGAAAGTCCTCTATCAAA
AATCCCATTATCCATAAAAAGGGCTCTATACTCGTTAATAGGACATATGAAGCGGAG
GAAAAAGATCAATTTGGGAACATCCAGATCGTCCGGAAAAATATACCTGAGAATAT
CTATCAAGAGCTGTACAAGTATTTTAATGATAAGTCAGACAAAGAGCTCAGTGATG
AGGCGGCAAAGCTCAAGAACGTGGTGGGGCATCATGAAGCTGCGACGAACATTGTC
AAAGATTATAGATACACTTACGATAAATACTTCCTCCACATGCCGATAACGATTAAC
TTCAAAGCCAATAAGACGGGGTTTATAAATGATCGGATCCTTCAGTACATTGCGAAA
GAGAAAGACCTCCATGTGATCGGAATTGACCGAGGAGAAAGGAATCTGATTTACGT
GTCCGTGATTGATACTTGCGGGAATATAGTCGAGCAAAAGAGTTTCAACATAGTCAA
CGGGTATGACTATCAGATAAAGCTCAAACAGCAGGAAGGTGCGAGGCAAATTGCGC
GCAAAGAGTGGAAGGAGATAGGCAAGATTAAAGAAATCAAGGAAGGTTATCTCAG
CTTGGTGATCCATGAAATATCTAAGATGGTTATAAAGTACAATGCCATAATAGCCAT
GGAGGATCTTTCCTACGGGTTTAAGAAGGGCCGATTTAAAGTGGAGCGACAAGTTT
ACCAGAAGTTCGAAACCATGTTGATTAACAAACTTAACTATTTGGTGTTCAAGGATA
TAAGTATAACCGAAAACGGCGGTTTGCTTAAGGGTTATCAGCTCACGTATATTCCTG
ATAAACTTAAAAACGTTGGACACCAGTGTGGATGTATCTTCTACGTGCCAGCCGCTT
ACACTAGTAAGATAGATCCTACCACGGGGTTTGTGAATATTTTTAAGTTTAAAGACT
TGACAGTCGACGCCAAAAGGGAATTTATAAAAAAGTTTGATTCTATCCGCTACGATA
GTGAAAAAAATCTCTTTTGCTTTACTTTCGACTATAACAACTTCATTACGCAGAACA
CTGTCATGAGTAAGTCCAGCTGGAGCGTCTACACATATGGCGTCCGAATTAAACGAC
GATTTGTAAACGGGCGGTTTTCAAACGAATCTGACACGATAGACATTACCAAGGAT
ATGGAGAAGACACTTGAGATGACCGACATAAACTGGCGGGACGGTCACGATCTTCG
GCAGGACATAATTGATTACGAAATCGTCCAGCATATATTCGAAATATTTCGACTTAC
AGTGCAAATGCGGAACAGTCTCTCTGAACTGGAAGATCGCGATTATGACCGGTTGAT
TTCTCCGGTCCTCAATGAAAATAACATATTTTATGATAGTGCTAAGGCAGGTGATGC
GTTGCCAAAGGATGCAGACGCTAATGGTGCCTATTGTATCGCGCTCAAGGGATTGTA
CGAGATAAAGCAAATTACGGAGAACTGGAAGGAGGATGGTAAGTTTAGCCGAGAC
AAGTTGAAGATTAGCAATAAAGACTGGTTTGATTTTATCCAAAACAAGAGGTACCTG
SEQ ID NO: 40
ATGAATAACGGAACTAATAACTTTCAAAATTTCATAGGTATTTCAAGCTTGCAGAAG
ACCCTGAGGAATGCCCTGATTCCAACCGAGACAACGCAGCAGTTCATAGTCAAAAA
TGGCATTATTAAGGAAGATGAGCTGCGGGGGGAAAACCGACAGATACTCAAGGATA
TTATGGACGACTATTACCGGGGATTTATCTCAGAAACGCTGAGCAGTATTGATGACA
TCGATTGGACCAGTCTTTTCGAGAAAATGGAAATTCAACTTAAGAATGGTGACAATA
AAGACACTCTCATAAAGGAGCAAACTGAATACCGAAAAGCCATACACAAAAAGTTT
GCCAACGATGACCGCTTTAAAAACATGTTTTCAGCTAAGCTCATTAGCGACATTCTC
CCCGAGTTTGTGATTCATAACAATAACTATAGCGCATCCGAGAAGGAGGAAAAAAC
CCAAGTTATCAAATTGTTCAGTAGATTCGCTACGAGCTTTAAAGATTACTTTAAAAA
CCGGGCTAACTGCTTCAGTGCAGACGATATCAGCTCCTCATCCTGTCATCGCATCGT
CAATGATAATGCTGAGATCTTCTTTTCTAATGCACTGGTTTACCGCAGGATAGTTAA
GTCTCTTAGTAACGACGACATCAACAAGATATCAGGAGATATGAAGGATTCCCTTAA
AGAAATGAGTCTCGAGGAGATATATTCTTATGAAAAATACGGCGAATTTATTACCCA
AGAGGGCATTAGTTTCTATAATGACATATGCGGAAAAGTTAATAGTTTTATGAATCT
CTATTGTCAGAAGAATAAGGAGAATAAGAACCTCTACAAATTGCAGAAGTTGCACA
AGCAAATTCTGTGTATCGCGGACACCTCTTACGAGGTCCCATATAAGTTCGAGAGTG
ATGAAGAAGTATACCAGAGCGTTAATGGGTTCCTGGACAACATCTCAAGTAAACAC
ATAGTCGAAAGGCTCCGAAAGATCGGTGATAACTATAACGGATATAATTTGGATAA
AATTTATATAGTTAGCAAATTTTACGAGAGCGTCAGTCAGAAGACCTACCGGGACTG
GGAGACCATAAACACAGCGCTGGAAATACATTATAACAACATACTGCCTGGGAACG
GTAAGTCAAAGGCAGACAAGGTTAAAAAGGCTGTGAAGAATGACCTGCAAAAATCA
ATTACAGAAATAAATGAGTTGGTAAGTAATTACAAACTTTGCAGCGATGATAATATA
AAGGCAGAGACGTACATACATGAAATATCTCATATCCTCAACAATTTCGAAGCCCA
AGAACTGAAGTACAACCCGGAAATTCATCTTGTAGAGTCTGAGTTGAAGGCCTCCG
AATTGAAAAACGTTCTTGACGTAATTATGAATGCCTTCCACTGGTGCTCAGTATTCA
TGACGGAAGAGCTCGTGGATAAAGACAACAATTTTTACGCTGAACTGGAAGAAATA
TATGACGAGATTTACCCCGTAATTTCACTCTACAACTTGGTACGAAATTACGTTACC
CAAAAGCCATACTCAACAAAAAAAATTAAACTGAACTTCGGGATACCCACCCTCGC
AGATGGATGGTCAAAGTCCAAAGAGTACAGTAACAATGCAATTATCCTGATGCGAG
ACAACCTTTATTACCTCGGGATTTTCAACGCTAAAAATAAACCTGATAAAAAAATAA
TTGAGGGTAATACCTCTGAAAACAAGGGGGATTATAAAAAGATGATATACAATCTG
CTGCCTGGCCCGAACAAAATGATTCCTAAAGTCTTCTTGTCTTCCAAGACTGGAGTC
GAAACCTACAAGCCAAGTGCTTATATACTCGAAGGGTACAAACAAAATAAGCACAT
AAAATCCAGCAAGGATTTTGATATTACATTCTGCCACGATTTGATTGATTATTTTAAG
AACTGTATAGCCATCCACCCAGAATGGAAGAATTTTGGTTTTGATTTTAGCGATACC
TCAACATATGAGGATATCTCTGGCTTTTACCGCGAGGTAGAACTGCAAGGTTATAAG
ATCGATTGGACTTATATTTCTGAAAAGGACATAGATCTCCTGCAAGAGAAAGGGCA
ACTTTATTTGTTTCAAATATACAACAAAGATTTTAGTAAGAAGAGTACTGGCAATGA
TAACCTTCACACTATGTATCTGAAGAACCTTTTTTCTGAGGAGAACTTGAAGGACAT
AGTCCTTAAACTCAATGGGGAAGCTGAAATATTCTTTCGCAAAAGCTCCATTAAAAA
CCCGATCATTCATAAAAAGGGTTCCATCTTGGTAAACCGCACATACGAGGCGGAAG
AAAAAGATCAGTTCGGAAATATCCAGATCGTAAGGAAGAATATCCCCGAAAATATA
TACCAAGAGCTTTACAAATATTTTAACGATAAGTCAGACAAGGAACTGTCAGACGA
AGCAGCCAAGTTGAAGAATGTCGTAGGGCACCACGAAGCAGCTACAAACATAGTTA
AAGATTATCGGTACACCTACGATAAATATTTCCTGCATATGCCAATAACCATAAACT
TCAAAGCCAACAAAACAGGGTTCATCAATGACCGAATACTTCAGTATATAGCCAAG
GAAAAAGACCTGCATGTTATAGGAATAGATAGAGGTGAGCGCAACTTGATATATGT
CAGCGTGATAGACACCTGCGGAAATATCGTCGAGCAAAAAAGTTTCAACATTGTTA
ATGGCTACGATTACCAAATTAAATTGAAGCAGCAAGAGGGGGCTCGGCAAATCGCG
CGAAAGGAATGGAAAGAAATCGGGAAGATTAAAGAAATTAAAGAGGGCTACCTGT
CTCTTGTAATTCACGAAATATCTAAGATGGTCATCAAGTATAATGCCATTATTGCGA
TGGAAGATCTGTCCTACGGATTTAAGAAAGGCAGGTTTAAAGTCGAAAGGCAGGTG
TACCAGAAATTCGAGACCATGCTGATTAATAAGCTCAACTATCTCGTATTTAAGGAT
ATTTCTATAACTGAAAATGGAGGGCTTCTCAAAGGATATCAACTCACATACATACCT
GATAAGCTGAAGAACGTAGGCCACCAGTGTGGATGCATATTCTATGTACCAGCTGC
ATACACAAGCAAGATCGATCCAACTACTGGGTTTGTCAATATCTTCAAATTTAAGGA
CTTGACGGTCGATGCCAAACGGGAGTTCATCAAAAAGTTTGATAGTATTCGATATGA
TAGTGAGAAGAACTTGTTTTGCTTCACATTTGACTACAACAATTTCATAACGCAAAA
TACGGTTATGTCTAAATCCTCATGGAGCGTCTACACTTACGGAGTGAGGATAAAGCG
GCGCTTCGTAAATGGCAGGTTTAGCAATGAATCCGACACGATTGACATAACCAAGG
ATATGGAGAAAACCCTCGAGATGACCGATATAAATTGGCGGGATGGACACGATCTG
CGACAAGACATAATCGATTATGAAATCGTGCAGCACATATTTGAGATATTCAGGCTT
ACGGTCCAAATGAGAAATTCCCTTTCCGAACTTGAAGACCGCGATTACGACCGACTG
ATAAGCCCCGTTCTGAACGAAAATAACATCTTCTACGACAGCGCTAAAGCGGGAGA
CGCGCTGCCGAAAGATGCGGACGCAAATGGAGCCTATTGTATCGCCTTGAAAGGGT
TGTACGAGATCAAACAGATAACCGAGAATTGGAAGGAGGATGGGAAGTTTAGTCGA
GACAAACTTAAAATAAGCAACAAGGACTGGTTCGACTTTATTCAAAACAAACGATA
TCTC
SEQ ID NO: 41
ATGAATAATGGTACTAACAATTTTCAAAACTTTATCGGCATCTCTTCACTTCAGAAA
ACTCTTCGGAACGCCCTTATACCGACGGAGACAACGCAGCAGTTTATAGTTAAAAAC
GGGATCATTAAAGAAGATGAACTCAGAGGGGAAAACAGGCAAATATTGAAGGACA
TTATGGACGATTACTACCGGGGGTTTATTTCAGAGACCCTTTCATCTATTGATGACAT
AGATTGGACCTCCCTTTTCGAGAAAATGGAGATACAATTGAAAAACGGCGACAATA
AAGATACACTTATCAAGGAACAAACTGAGTATCGCAAGGCGATTCACAAGAAGTTT
GCGAATGACGATCGCTTTAAGAATATGTTTTCTGCGAAGCTCATAAGTGACATTCTG
CCTGAATTTGTCATTCATAACAACAATTATTCTGCTAGCGAAAAAGAGGAAAAAACT
CAAGTCATTAAGCTTTTTAGCAGGTTCGCTACTAGTTTTAAAGACTATTTTAAGAACC
GGGCGAATTGCTTTAGCGCTGACGACATATCATCCTCATCCTGTCATCGCATAGTCA
ATGATAATGCAGAAATATTCTTTTCTAATGCGCTCGTGTATCGGAGAATAGTGAAAA
GCCTCTCTAACGATGACATTAACAAAATAAGCGGCGATATGAAGGATAGTCTGAAG
GAAATGTCCCTCGAAGAAATATACTCATACGAGAAGTACGGAGAATTTATCACCCA
GGAAGGAATTAGTTTTTACAACGACATCTGTGGTAAGGTTAACTCTTTTATGAATCT
GTATTGTCAAAAGAATAAAGAAAATAAAAATCTTTATAAGCTCCAAAAGCTTCACA
AACAAATCTTGTGCATTGCGGATACGTCATACGAAGTACCTTACAAATTTGAAAGCG
ACGAAGAGGTGTATCAGTCAGTGAATGGGTTCCTTGACAATATTTCTAGCAAACATA
TTGTGGAGCGACTTCGAAAGATCGGTGATAATTACAATGGCTATAATTTGGATAAAA
TTTACATAGTTAGTAAGTTTTATGAATCCGTCTCACAAAAGACGTACCGAGATTGGG
AGACCATCAACACTGCTCTGGAGATTCATTACAATAATATATTGCCTGGGAATGGGA
AGTCAAAGGCCGACAAGGTTAAAAAAGCCGTAAAAAACGATCTTCAAAAGTCCATT
ACCGAGATAAATGAACTTGTATCCAACTATAAGTTGTGCTCTGACGATAATATTAAA
GCAGAAACGTATATCCACGAAATAAGTCACATCCTGAACAACTTCGAAGCTCAAGA
GCTCAAGTATAATCCTGAAATTCATCTCGTCGAAAGCGAGCTGAAAGCATCCGAGTT
GAAGAATGTGCTTGATGTGATCATGAACGCATTCCATTGGTGCAGTGTGTTCATGAC
CGAAGAACTTGTAGACAAAGACAACAACTTCTACGCTGAATTGGAAGAGATTTACG
ATGAAATTTACCCCGTGATATCCCTCTATAATCTGGTAAGAAATTACGTCACGCAAA
AACCATACAGTACCAAGAAAATAAAGCTCAACTTTGGTATTCCGACGTTGGCAGAT
GGGTGGAGTAAGAGCAAGGAGTATTCTAACAATGCAATCATCCTCATGCGCGACAA
TTTGTATTATCTGGGGATCTTCAACGCGAAAAATAAGCCCGACAAAAAGATAATAG
AAGGCAATACGTCCGAGAACAAAGGGGACTATAAGAAAATGATTTATAACCTTCTT
CCAGGACCCAACAAGATGATCCCAAAGGTTTTCTTGAGTTCAAAAACCGGCGTAGA
AACTTATAAACCGTCCGCCTACATTCTGGAAGGGTACAAGCAAAACAAGCACATTA
AGTCATCTAAGGATTTCGACATTACTTTTTGTCATGATTTGATAGACTACTTCAAAAA
TTGTATAGCGATACATCCGGAATGGAAAAATTTTGGGTTCGATTTTTCCGACACAAG
TACTTATGAAGACATCTCAGGGTTTTATAGGGAAGTTGAACTGCAAGGTTACAAAAT
AGACTGGACTTATATTAGTGAGAAGGACATTGATTTGCTCCAGGAAAAGGGTCAATT
GTATCTGTTCCAGATATATAACAAGGATTTCTCTAAAAAATCTACAGGTAACGACAA
TCTCCACACGATGTACCTCAAGAATCTCTTCAGCGAAGAGAATTTGAAGGATATCGT
ACTTAAGCTCAATGGAGAAGCGGAAATATTCTTCAGAAAGTCCAGCATTAAGAATC
CTATAATTCACAAGAAAGGGTCAATTCTCGTAAACCGGACTTATGAGGCCGAAGAA
AAAGATCAGTTTGGTAACATTCAGATTGTACGGAAAAACATTCCCGAGAACATCTAT
CAAGAACTGTATAAATACTTTAATGATAAATCCGACAAGGAACTTTCTGACGAGGCT
GCAAAATTGAAGAACGTAGTGGGACACCATGAGGCCGCAACCAATATAGTAAAGGA
TTACAGATACACTTATGATAAGTATTTCCTCCATATGCCGATCACGATTAATTTCAAG
GCGAATAAAACCGGCTTCATTAACGATCGCATTTTGCAATATATTGCGAAGGAAAA
GGATTTGCACGTGATAGGTATAGACCGGGGTGAACGAAACTTGATTTACGTCTCTGT
GATCGACACATGCGGAAATATAGTTGAACAGAAGTCCTTTAATATTGTGAATGGTTA
CGACTACCAGATAAAATTGAAGCAACAGGAGGGCGCAAGACAGATAGCTCGCAAA
GAGTGGAAGGAAATCGGCAAGATCAAAGAAATAAAGGAGGGTTATCTTTCCCTGGT
AATTCATGAAATTAGCAAGATGGTTATTAAGTATAATGCTATAATAGCTATGGAGGA
CCTTTCCTATGGGTTCAAGAAAGGTCGCTTCAAAGTGGAGCGACAAGTGTATCAAAA
GTTCGAGACTATGTTGATAAATAAATTGAATTATTTGGTTTTTAAAGACATTTCAATA
ACTGAGAACGGGGGTCTCTTGAAGGGGTACCAATTGACTTATATTCCGGACAAGTTG
AAGAATGTCGGACACCAGTGTGGTTGCATTTTCTACGTGCCTGCCGCTTACACCTCA
AAAATCGATCCGACCACTGGTTTTGTAAATATATTTAAATTCAAAGATCTCACCGTT
GATGCCAAACGGGAGTTTATCAAAAAATTCGATTCCATTCGCTACGACTCTGAGAAA
AACCTTTTTTGTTTCACGTTCGATTATAACAACTTTATAACCCAAAATACTGTAATGT
CCAAGTCAAGTTGGTCTGTCTATACTTACGGAGTAAGGATCAAGCGCCGCTTCGTTA
ATGGGAGATTCTCAAACGAGTCTGATACCATAGACATAACTAAAGACATGGAAAAA
ACCCTGGAAATGACGGACATCAATTGGCGAGACGGGCATGATCTTCGACAGGACAT
AATAGATTACGAAATTGTTCAACACATTTTCGAGATATTTCGACTTACGGTTCAGAT
GAGGAATTCCCTTTCCGAATTGGAAGACCGGGATTATGATCGACTTATATCTCCCGT
GCTCAATGAAAACAATATTTTTTATGATTCAGCGAAAGCTGGGGACGCGCTGCCAAA
AGATGCCGATGCCAATGGAGCATACTGTATCGCCCTGAAGGGTTTGTATGAGATTAA
GCAAATTACTGAAAACTGGAAGGAAGATGGCAAGTTTTCTAGAGATAAGCTTAAGA
TTAGCAATAAGGACTGGTTTGACTTCATTCAAAATAAAAGGTATCTT
SEQ ID NO: 42
ATGAATAATGGAACAAATAATTTTCAAAATTTTATTGGTATCAGTTCATTGCAAAAG
ACTTTGAGAAATGCTTTGATCCCGACTGAGACCACACAGCAGTTCATCGTCAAAAAT
GGCATAATCAAGGAAGACGAACTTAGGGGTGAGAATAGACAAATATTGAAGGACAT
CATGGATGACTATTATAGGGGGTTCATTTCCGAAACGCTCAGTAGTATTGATGACAT
TGACTGGACTAGTCTTTTCGAGAAAATGGAAATTCAGCTTAAGAACGGGGACAATA
AAGACACGCTGATCAAGGAGCAAACGGAATATAGGAAGGCGATCCATAAAAAATTC
GCGAATGATGATCGGTTTAAAAACATGTTTAGTGCCAAGTTGATCAGCGACATACTG
CCCGAATTCGTGATCCACAACAATAATTACAGCGCCTCCGAAAAGGAGGAAAAAAC
TCAGGTCATTAAATTGTTTAGCCGATTCGCAACGAGTTTCAAAGATTATTTTAAGAA
CCGGGCCAACTGTTTTTCAGCGGATGATATTAGCTCCAGCAGCTGCCATCGCATAGT
AAATGATAACGCTGAAATCTTTTTTAGCAACGCACTTGTCTACCGGAGGATTGTAAA
ATCACTGTCAAATGATGACATTAACAAAATATCTGGAGATATGAAGGACTCACTCA
AAGAAATGAGCCTGGAAGAAATATATTCATACGAAAAATACGGGGAGTTTATTACC
CAGGAAGGTATCAGTTTTTATAATGATATATGTGGAAAAGTTAATTCATTTATGAAT
CTTTACTGTCAAAAAAATAAGGAGAACAAGAATTTGTACAAGCTCCAAAAACTTCA
TAAACAGATTCTGTGCATCGCAGACACAAGTTATGAGGTACCGTACAAATTTGAGA
GCGACGAAGAAGTTTATCAGAGTGTGAATGGTTTCCTGGACAATATCTCTTCTAAAC
ACATTGTTGAGAGGCTTAGGAAGATCGGTGATAATTATAACGGCTATAATCTGGACA
AAATTTATATTGTATCAAAGTTTTATGAATCAGTCTCTCAAAAGACGTATCGGGATT
GGGAAACAATTAACACGGCTCTGGAGATCCACTACAATAACATTCTGCCCGGCAAC
GGGAAGAGCAAAGCTGATAAGGTCAAGAAGGCAGTCAAGAACGACCTTCAGAAGA
GCATAACAGAAATTAACGAATTGGTCAGTAACTACAAACTGTGTAGTGATGACAAC
ATAAAAGCCGAAACATACATCCATGAAATAAGCCATATCCTGAATAACTTCGAAGC
CCAAGAACTTAAATACAATCCCGAGATTCATCTTGTCGAATCAGAACTCAAGGCGTC
CGAGCTCAAAAATGTCCTTGACGTGATAATGAATGCCTTCCACTGGTGCAGCGTATT
CATGACGGAGGAGTTGGTAGATAAAGACAACAACTTTTATGCCGAATTGGAAGAGA
TTTATGATGAGATTTACCCCGTTATTTCTCTGTACAACTTGGTTCGAAACTACGTAAC
ACAAAAACCATACTCAACCAAAAAGATCAAACTCAATTTTGGCATACCTACATTGGC
TGATGGTTGGTCCAAGTCAAAGGAATATAGCAATAATGCAATAATTCTCATGCGAG
ATAACTTGTATTATTTGGGGATCTTTAACGCTAAGAACAAACCAGATAAAAAGATAA
TCGAGGGGAACACAAGTGAGAACAAGGGTGATTACAAAAAAATGATTTACAATCTG
CTTCCTGGGCCTAACAAAATGATTCCGAAGGTGTTTCTTAGCTCTAAAACTGGAGTG
GAGACGTATAAGCCTTCCGCGTACATTCTCGAAGGCTACAAGCAAAATAAGCATAT
CAAGTCCAGTAAGGACTTCGACATCACTTTTTGCCACGATCTCATCGATTACTTTAA
GAACTGTATCGCAATACACCCCGAGTGGAAAAACTTTGGTTTTGATTTTTCAGACAC
TAGTACCTACGAGGACATTTCCGGCTTCTATCGAGAAGTCGAACTCCAGGGCTACAA
AATCGATTGGACGTACATTTCTGAGAAGGACATCGACTTGCTCCAAGAGAAAGGTC
AACTTTACCTCTTCCAAATTTACAATAAAGACTTTTCAAAGAAGAGCACCGGTAATG
ACAACTTGCATACCATGTATCTGAAGAACCTGTTTTCTGAGGAGAACCTCAAGGATA
TTGTATTGAAGTTGAATGGCGAAGCAGAAATATTTTTCCGAAAGTCATCTATCAAGA
ACCCCATTATACACAAAAAAGGCTCTATCCTGGTGAACCGGACTTACGAGGCAGAG
GAGAAGGATCAATTCGGAAACATACAGATAGTCCGCAAAAACATCCCTGAGAATAT
CTATCAGGAACTCTATAAGTACTTCAATGATAAATCAGACAAGGAGCTTAGCGACG
AAGCAGCTAAACTTAAAAACGTGGTTGGCCATCACGAGGCCGCTACCAACATAGTC
AAAGACTACCGCTATACTTATGACAAGTACTTTTTGCACATGCCCATAACAATTAAT
TTCAAAGCTAACAAAACAGGGTTTATAAATGACAGAATCCTCCAATACATCGCCAA
AGAGAAGGACCTCCATGTAATCGGGATTGATAGAGGCGAACGGAACTTGATTTACG
TTAGTGTCATTGATACCTGTGGTAACATTGTCGAACAAAAGTCATTCAACATAGTCA
ATGGATATGATTATCAGATAAAACTCAAGCAACAAGAAGGCGCGAGGCAGATTGCC
AGGAAGGAATGGAAAGAAATCGGGAAGATCAAGGAGATCAAGGAGGGTTACCTGT
CCTTGGTGATACACGAGATTTCAAAAATGGTTATAAAATACAATGCCATTATCGCGA
TGGAGGATTTGTCTTATGGATTTAAGAAGGGGAGGTTCAAAGTCGAACGACAAGTC
TATCAGAAGTTTGAAACAATGCTCATTAACAAGCTCAATTACCTTGTTTTCAAGGAT
ATAAGCATCACTGAAAACGGCGGACTCCTTAAGGGATATCAGCTGACTTATATCCCC
GACAAGCTCAAGAACGTAGGGCACCAATGCGGATGCATCTTTTACGTGCCTGCAGC
ATATACTTCAAAAATTGATCCGACTACTGGCTTTGTTAACATTTTCAAGTTCAAGGAT
CTGACGGTAGACGCTAAGAGAGAATTCATAAAAAAGTTTGACAGCATCAGGTACGA
TAGTGAAAAGAACCTTTTTTGTTTTACCTTTGACTACAATAATTTTATTACGCAAAAT
ACAGTTATGAGCAAATCAAGTTGGAGCGTTTACACATATGGCGTTCGGATCAAGCGC
AGATTCGTCAATGGTCGCTTCTCAAATGAGAGCGATACAATCGATATAACGAAGGA
TATGGAGAAGACGCTTGAGATGACAGATATCAACTGGCGGGACGGACATGACCTTA
GACAAGACATAATCGATTACGAAATAGTACAGCATATCTTTGAGATTTTTAGGCTTA
CAGTTCAGATGCGGAACTCTCTTTCCGAACTGGAGGACCGGGATTATGATCGGTTGA
TCTCCCCAGTACTGAACGAAAATAATATCTTTTACGATAGCGCGAAGGCTGGTGATG
CACTCCCAAAAGACGCTGATGCGAACGGAGCTTATTGCATAGCCCTTAAAGGGCTTT
ACGAGATTAAACAAATAACAGAAAATTGGAAGGAAGATGGCAAATTTTCCCGCGAC
AAGTTGAAGATTAGTAACAAAGACTGGTTCGACTTCATTCAGAATAAACGCTACCTC
Nucleic acid-guided nucleases can encompass a native sequence, an engineered sequence, or engineered nucleotide sequences of synthetized variants. Non-limiting examples of types of engineering that can be done to obtain a non-naturally occurring nuclease system are as follows. Engineering can include codon optimization to facilitate expression or improve expression in a host cell, such as a heterologous host cell. Engineering can reduce the size or molecular weight of the nuclease in order to facilitate expression or delivery. Engineering can alter PAM selection in order to change PAM specificity or to broaden the range of recognized PAMs. Engineering can alter, increase, or decrease stability, processivity, specificity, or efficiency of a targetable nuclease system. Engineering can alter, increase, or decrease protein stability. Engineering can alter, increase, or decrease processivity of nucleic acid scanning. Engineering can alter, increase, or decrease target sequence specificity. Engineering can alter, increase, or decrease nuclease activity. Engineering can alter, increase, or decrease editing efficiency. Engineering can alter, increase, or decrease transformation efficiency. Engineering can alter, increase, or decrease nuclease or guide nucleic acid expression. As used herein, a non-naturally occurring nucleic acid sequence can be an engineered sequence or engineered nucleotide sequences of synthetized variants. Such non-naturally occurring nucleic acid sequences can be amplified, cloned, assembled, synthesized, generated from synthesized oligonucleotides or dNTPs, or otherwise obtained using methods known by those skilled in the art. In certain embodiments, examples of non-naturally occurring nucleic acid-guided nucleases disclosed herein can include those nucleic acid-guided nucleases with engineered polypeptide sequences (e.g., SEQ ID NOs:2-4) and those nucleotide sequences of synthetized variants (e.g., SEQ ID NOs: 43-63).
SEQ ID NO: 2
MGHHHHHHSSGVDLGTENLYFQSPAAKKKKLDGSVDMNNGTNNFQNFIGISSLQKTLR
NALIPTETTQQFIVKNGIIKEDELRGENRQILKDIMDDYYRGFISETLSSIDDIDWTSLFEK
MEIQLKNGDNKDTLIKEQTEYRKAIHKKFANDDRFKNMFSAKLISDILPEFVIHNNNYSA
SEKEEKTQVIKLFSRFATSFKDYFKNRANCFSADDISSSSCHRIVNDNAEIFFSNALVYRRI
VKSLSNDDINKISGDMKDSLKEMSLEEIYSYEKYGEFITQEGISFYNDICGKVNSFMNLY
CQKNKENKNLYKLQKLHKQILCIADTSYEVPYKFESDEEVYQSVNGFLDNISSKHIVERL
RKIGDNYNGYNLDKIYIVSKFYESVSQKTYRDWETINTALEIHYNNILPGNGKSKADKV
KKAVKNDLQKSITEINELVSNYKLCSDDNIKAETYIHEISHILNNFEAQELKYNPEIHLVE
SELKASELKNVLDVIMNAFHWCSVFMTEELVDKDNNFYAELEEIYDEIYPVISLYNLVR
NYVTQKPYSTKKIKLNFGIPTLADGWSKSKEYSNNAIILMRDNLYYLGIFNAKNKPDKKI
IEGNTSENKGDYKKMIYNLLPGPNKMIPKVFLSSKTGVETYKPSAYILEGYKQNKHIKSS
KDFDITFCHDLIDYFKNCIAIHPEWKNFGFDFSDTSTYEDISGFYREVELQGYKIDWTYIS
EKDIDLLQEKGQLYLFQIYNKDFSKKSTGNDNLHTMYLKNLFSEENLKDIVLKLNGEAEI
FFRKSSIKNPIIHKKGSILVNRTYEAEEKDQFGNIQIVRKNIPENIYQELYKYFNDKSDKEL
SDEAAKLKNVVGHHEAATNIVKDYRYTYDKYFLHMPITINFKANKTGFINDRILQYIAK
EKDLHVIGIDRGERNLIYVSVIDTCGNIVEQKSFNIVNGYDYQIKLKQQEGARQIARKEW
KEIGKIKEIKEGYLSLVIHEISKMVIKYNAIIAMEDLSYGFKKGRFKVERQVYQKFETMLI
NKLNYLVFKDISITENGGLLKGYQLTYIPDKLKNVGHQCGCIFYVPAAYTSKIDPTTGFV
NIFKFKDLTVDAKREFIKKFDSIRYDSEKNLFCFTFDYNNFITQNTVMSKSSWSVYTYGV
RIKRRFVNGRFSNESDTIDITKDMEKTLEMTDINWRDGHDLRQDIIDYEIVQHIFEIFRLTV
QMRNSLSELEDRDYDRLISPVLNENNIFYDSAKAGDALPKDADANGAYCIALKGLYEIK
QITENWKEDGKFSRDKLKISNKDWFDFIQNKRYLKRPAATKKAGQAKKKKASGSGAGS
PKKKRKVEDPKKKRKVIPG*
SEQ ID NO: 3
SPAAKKKKLDGSVDMNNGTNNFQNFIGISSLQKTLRNALIPTETTQQFIVKNGIIKEDELR
GENRQILKDIMDDYYRGFISETLSSIDDIDWTSLFEKMEIQLKNGDNKDTLIKEQTEYRK
AIHKKFANDDRFKNMFSAKLISDILPEFVIHNNNYSASEKEEKTQVIKLFSRFATSFKDYF
KNRANCFSADDISSSSCHRIVNDNAEIFFSNALVYRRIVKSLSNDDINKISGDMKDSLKEM
SLEEIYSYEKYGEFITQEGISFYNDICGKVNSFMNLYCQKNKENKNLYKLQKLHKQILCI
ADTSYEVPYKFESDEEVYQSVNGFLDNISSKHIVERLRKIGDNYNGYNLDKIYIVSKFYE
SVSQKTYRDWETINTALEIHYNNILPGNGKSKADKVKKAVKNDLQKSITEINELVSNYK
LCSDDNIKAETYIHEISHILNNFEAQELKYNPEIHLVESELKASELKNVLDVIMNAFHWCS
VFMTEELVDKDNNFYAELEEIYDEIYPVISLYNLVRNYVTQKPYSTKKIKLNFGIPTLAD
GWSKSKEYSNNAIILMRDNLYYLGIFNAKNKPDKKIIEGNTSENKGDYKKMIYNLLPGP
NKMIPKVFLSSKTGVETYKPSAYILEGYKQNKHIKSSKDFDITFCHDLIDYFKNCIAIHPE
WKNFGFDFSDTSTYEDISGFYREVELQGYKIDWTYISEKDIDLLQEKGQLYLFQIYNKDF
SKKSTGNDNLHTMYLKNLFSEENLKDIVLKLNGEAEIFFRKSSIKNPIIHKKGSILVNRTY
EAEEKDQFGNIQIVRKNIPENIYQELYKYFNDKSDKELSDEAAKLKNVVGHHEAATNIV
KDYRYTYDKYFLHMPITINFKANKTGFINDRILQYIAKEKDLHVIGIDRGERNLIYVSVID
TCGNIVEQKSFNIVNGYDYQIKLKQQEGARQIARKEWKEIGKIKEIKEGYLSLVIHEISKM
VIKYNAIIAMEDLSYGFKKGRFKVERQVYQKFETMLINKLNYLVFKDISITENGGLLKGY
QLTYIPDKLKNVGHQCGCIFYVPAAYTSKIDPTTGFVNIFKFKDLTVDAKREFIKKFDSIR
YDSEKNLFCFTFDYNNFITQNTVMSKSSWSVYTYGVRIKRRFVNGRFSNESDTIDITKDM
EKTLEMTDINWRDGHDLRQDIIDYEIVQHIFEIFRLTVQMRNSLSELEDRDYDRLISPVLN
ENNIFYDSAKAGDALPKDADANGAYCIALKGLYEIKQITENWKEDGKFSRDKLKISNKD
WFDFIQNKRYLKRPAATKKAGQAKKKKASGSGAGSPKKKRKVEDPKKKRKVIPG*
SEQ ID NO: 4
PAAKKKKLDGSVDMNNGTNNFQNFIGISSLQKTLRNALIPTETTQQFIVKNGIIKEDELRG
ENRQILKDIMDDYYRGFISETLSSIDDIDWTSLFEKMEIQLKNGDNKDTLIKEQTEYRKAI
HKKFANDDRFKNMFSAKLISDILPEFVIHNNNYSASEKEEKTQVIKLFSRFATSFKDYFK
NRANCFSADDISSSSCHRIVNDNAEIFFSNALVYRRIVKSLSNDDINKISGDMKDSLKEMS
LEEIYSYEKYGEFITQEGISFYNDICGKVNSFMNLYCQKNKENKNLYKLQKLHKQILCIA
DTSYEVPYKFESDEEVYQSVNGFLDNISSKHIVERLRKIGDNYNGYNLDKIYIVSKFYES
VSQKTYRDWETINTALEIHYNNILPGNGKSKADKVKKAVKNDLQKSITEINELVSNYKL
CSDDNIKAETYIHEISHILNNFEAQELKYNPEIHLVESELKASELKNVLDVIMNAFHWCSV
FMTEELVDKDNNFYAELEEIYDEIYPVISLYNLVRNYVTQKPYSTKKIKLNFGIPTLADG
WSKSKEYSNNAIILMRDNLYYLGIFNAKNKPDKKIIEGNTSENKGDYKKMIYNLLPGPN
KMIPKVFLSSKTGVETYKPSAYILEGYKQNKHIKSSKDFDITFCHDLIDYFKNCIAIHPEW
KNFGFDFSDTSTYEDISGFYREVELQGYKIDWTYISEKDIDLLQEKGQLYLFQIYNKDFSK
KSTGNDNLHTMYLKNLFSEENLKDIVLKLNGEAEIFFRKSSIKNPIIHKKGSILVNRTYEA
EEKDQFGNIQIVRKNIPENIYQELYKYFNDKSDKELSDEAAKLKNVVGHHEAATNIVKD
YRYTYDKYFLHMPITINFKANKTGFINDRILQYIAKEKDLHVIGIDRGERNLIYVSVIDTC
GNIVEQKSFNIVNGYDYQIKLKQQEGARQIARKEWKEIGKIKEIKEGYLSLVIHEISKMVI
KYNAIIAMEDLSYGFKKGRFKVERQVYQKFETMLINKLNYLVFKDISITENGGLLKGYQ
LTYIPDKLKNVGHQCGCIFYVPAAYTSKIDPTTGFVNIFKFKDLTVDAKREFIKKFDSIRY
DSEKNLFCFTFDYNNFITQNTVMSKSSWSVYTYGVRIKRRFVNGRFSNESDTIDITKDME
KTLEMTDINWRDGHDLRQDIIDYEIVQHIFEIFRLTVQMRNSLSELEDRDYDRLISPVLNE
NNIFYDSAKAGDALPKDADANGAYCIALKGLYEIKQITENWKEDGKFSRDKLKISNKD
WFDFIQNKRYLKRPAATKKAGQAKKKKASGSGAGSPKKKRKVEDPKKKRKVIPG*
SEQ ID NO: 109:
SMSRRRKANPTKLSENAKKLAKEVENASGSGAGSKRPAATKKAGQAKKKKASGSGAG
SPAAKKKKLDGSVDASGSGAGSPKKKRKVEDASGSGAGSPKKKRKVASGSGAGSMNN
GTNNFQNFIGISSLQKTLRNALIPTETTQQFIVKNGIIKEDELRGENRQILKDIMDDYYRGF
ISETLSSIDDIDWTSLFEKMEIQLKNGDNKDTLIKEQTEYRKAIHKKFANDDRFKNMFSA
KLISDILPEFVIHNNNYSASEKEEKTQVIKLFSRFATSFKDYFKNRANCFSADDISSSSCHR
IVNDNAEIFFSNALVYRRIVKSLSNDDINKISGDMKDSLKEMSLEEIYSYEKYGEFITQEGI
SFYNDICGKVNSFMNLYCQKNKENKNLYKLQKLHKQILCIADTSYEVPYKFESDEEVYQ
SVNGFLDNISSKHIVERLRKIGDNYNGYNLDKIYIVSKFYESVSQKTYRDWETINTALEIH
YNNILPGNGKSKADKVKKAVKNDLQKSITEINELVSNYKLCSDDNIKAETYIHEISHILN
NFEAQELKYNPEIHLVESELKASELKNVLDVIMNAFHWCSVFMTEELVDKDNNFYAELE
EIYDEIYPVISLYNLVRNYVTQKPYSTKKIKLNFGIPTLADGWSKSKEYSNNAIILMRDNL
YYLGIFNAKNKPDKKIIEGNTSENKGDYKKMIYNLLPGPNKMIPKVFLSSKTGVETYKPS
AYILEGYKQNKHIKSSKDFDITFCHDLIDYFKNCIAIHPEWKNFGFDFSDTSTYEDISGFY
REVELQGYKIDWTYISEKDIDLLQEKGQLYLFQIYNKDFSKKSTGNDNLHTMYLKNLFS
EENLKDIVLKLNGEAEIFFRKSSIKNPIIHKKGSILVNRTYEAEEKDQFGNIQIVRKNIPENI
YQELYKYFNDKSDKELSDEAAKLKNVVGHHEAATNIVKDYRYTYDKYFLHMPITINFK
ANKTGFINDRILQYIAKEKDLHVIGIDRGERNLIYVSVIDTCGNIVEQKSFNIVNGYDYQI
KLKQQEGARQIARKEWKEIGKIKEIKEGYLSLVIHEISKMVIKYNAIIAMEDLSYGFKKG
RFKVERQVYQKFETMLINKLNYLVFKDISITENGGLLKGYQLTYIPDKLKNVGHQCGCIF
YVPAAYTSKIDPTTGFVNIFKFKDLTVDAKREFIKKFDSIRYDSEKNLFCFTFDYNNFITQ
NTVMSKSSWSVYTYGVRIKRRFVNGRFSNESDTIDITKDMEKTLEMTDINWRDGHDLR
QDIIDYEIVQHIFEIFRLTVQMRNSLSELEDRDYDRLISPVLNENNIFYDSAKAGDALPKD
ADANGAYCIALKGLYEIKQITENWKEDGKFSRDKLKISNKDWFDFIQNKRYL
SEQ ID NO: 110:
MSRRRKANPTKLSENAKKLAKEVENASGSGAGSKRPAATKKAGQAKKKKASGSGAGS
PAAKKKKLDGSVDASGSGAGSPKKKRKVEDASGSGAGSPKKKRKVASGSGAGSMNNG
TNNFQNFIGISSLQKTLRNALIPTETTQQFIVKNGIIKEDELRGENRQILKDIMDDYYRGFI
SETLSSIDDIDWTSLFEKMEIQLKNGDNKDTLIKEQTEYRKAIHKKFANDDRFKNMFSAK
LISDILPEFVIHNNNYSASEKEEKTQVIKLFSRFATSFKDYFKNRANCFSADDISSSSCHRI
VNDNAEIFFSNALVYRRIVKSLSNDDINKISGDMKDSLKEMSLEEIYSYEKYGEFITQEGI
SFYNDICGKVNSFMNLYCQKNKENKNLYKLQKLHKQILCIADTSYEVPYKFESDEEVYQ
SVNGFLDNISSKHIVERLRKIGDNYNGYNLDKIYIVSKFYESVSQKTYRDWETINTALEIH
YNNILPGNGKSKADKVKKAVKNDLQKSITEINELVSNYKLCSDDNIKAETYIHEISHILN
NFEAQELKYNPEIHLVESELKASELKNVLDVIMNAFHWCSVFMTEELVDKDNNFYAELE
EIYDEIYPVISLYNLVRNYVTQKPYSTKKIKLNFGIPTLADGWSKSKEYSNNAIILMRDNL
YYLGIFNAKNKPDKKIIEGNTSENKGDYKKMIYNLLPGPNKMIPKVFLSSKTGVETYKPS
AYILEGYKQNKHIKSSKDFDITFCHDLIDYFKNCIAIHPEWKNFGFDFSDTSTYEDISGFY
REVELQGYKIDWTYISEKDIDLLQEKGQLYLFQIYNKDFSKKSTGNDNLHTMYLKNLFS
EENLKDIVLKLNGEAEIFFRKSSIKNPIIHKKGSILVNRTYEAEEKDQFGNIQIVRKNIPENI
YQELYKYFNDKSDKELSDEAAKLKNVVGHHEAATNIVKDYRYTYDKYFLHMPITINFK
ANKTGFINDRILQYIAKEKDLHVIGIDRGERNLIYVSVIDTCGNIVEQKSFNIVNGYDYQI
KLKQQEGARQIARKEWKEIGKIKEIKEGYLSLVIHEISKMVIKYNAIIAMEDLSYGFKKG
RFKVERQVYQKFETMLINKLNYLVFKDISITENGGLLKGYQLTYIPDKLKNVGHQCGCIF
YVPAAYTSKIDPTTGFVNIFKFKDLTVDAKREFIKKFDSIRYDSEKNLFCFTFDYNNFITQ
NTVMSKSSWSVYTYGVRIKRRFVNGRFSNESDTIDITKDMEKTLEMTDINWRDGHDLR
QDIIDYEIVQHIFEIFRLTVQMRNSLSELEDRDYDRLISPVLNENNIFYDSAKAGDALPKD
ADANGAYCIALKGLYEIKQITENWKEDGKFSRDKLKISNKDWFDFIQNKRYL
SEQ ID NO: 111
GHHHHHHSSGVDLGTENLYFQSMSRRRKANPTKLSENAKKLAKEVENASGSGAGSKRP
AATKKAGQAKKKKASGSGAGSPAAKKKKLDGSVDASGSGAGSPKKKRKVEDASGSGA
GSPKKKRKVASGSGAGSMNNGTNNFQNFIGISSLQKTLRNALIPTETTQQFIVKNGIIKED
ELRGENRQILKDIMDDYYRGFISETLSSIDDIDWTSLFEKMEIQLKNGDNKDTLIKEQTEY
RKAIHKKFANDDRFKNMFSAKLISDILPEFVIHNNNYSASEKEEKTQVIKLFSRFATSFKD
YFKNRANCFSADDISSSSCHRIVNDNAEIFFSNALVYRRIVKSLSNDDINKISGDMKDSLK
EMSLEEIYSYEKYGEFITQEGISFYNDICGKVNSFMNLYCQKNKENKNLYKLQKLHKQIL
CIADTSYEVPYKFESDEEVYQSVNGFLDNISSKHIVERLRKIGDNYNGYNLDKIYIVSKFY
ESVSQKTYRDWETINTALEIHYNNILPGNGKSKADKVKKAVKNDLQKSITEINELVSNY
KLCSDDNIKAETYIHEISHILNNFEAQELKYNPEIHLVESELKASELKNVLDVIMNAFHW
CSVFMTEELVDKDNNFYAELEEIYDEIYPVISLYNLVRNYVTQKPYSTKKIKLNFGIPTLA
DGWSKSKEYSNNAIILMRDNLYYLGIFNAKNKPDKKIIEGNTSENKGDYKKMIYNLLPG
PNKMIPKVFLSSKTGVETYKPSAYILEGYKQNKHIKSSKDFDITFCHDLIDYFKNCIAIHPE
WKNFGFDFSDTSTYEDISGFYREVELQGYKIDWTYISEKDIDLLQEKGQLYLFQIYNKDF
SKKSTGNDNLHTMYLKNLFSEENLKDIVLKLNGEAEIFFRKSSIKNPIIHKKGSILVNRTY
EAEEKDQFGNIQIVRKNIPENIYQELYKYFNDKSDKELSDEAAKLKNVVGHHEAATNIV
KDYRYTYDKYFLHMPITINFKANKTGFINDRILQYIAKEKDLHVIGIDRGERNLIYVSVID
TCGNIVEQKSFNIVNGYDYQIKLKQQEGARQIARKEWKEIGKIKEIKEGYLSLVIHEISKM
VIKYNAIIAMEDLSYGFKKGRFKVERQVYQKFETMLINKLNYLVFKDISITENGGLLKGY
QLTYIPDKLKNVGHQCGCIFYVPAAYTSKIDPTTGFVNIFKFKDLTVDAKREFIKKFDSIR
YDSEKNLFCFTFDYNNFITQNTVMSKSSWSVYTYGVRIKRRFVNGRFSNESDTIDITKDM
EKTLEMTDINWRDGHDLRQDIIDYEIVQHIFEIFRLTVQMRNSLSELEDRDYDRLISPVLN
ENNIFYDSAKAGDALPKDADANGAYCIALKGLYEIKQITENWKEDGKFSRDKLKISNKD
WFDFIQNKRYL*
SEQ ID NO: 112
MGHHHHHHSSGVDLGTENLYFQSMSRRRKANPTKLSENAKKLAKEVENASGSGAGSK
RPAATKKAGQAKKKKASGSGAGSPAAKKKKLDGSVDASGSGAGSPKKKRKVEDASGS
GAGSPKKKRKVASGSGAGSMNNGTNNFQNFIGISSLQKTLRNALIPTETTQQFIVKNGIIK
EDELRGENRQILKDIMDDYYRGFISETLSSIDDIDWTSLFEKMEIQLKNGDNKDTLIKEQT
EYRKAIHKKFANDDRFKNMFSAKLISDILPEFVIHNNNYSASEKEEKTQVIKLFSRFATSF
KDYFKNRANCFSADDISSSSCHRIVNDNAEIFFSNALVYRRIVKSLSNDDINKISGDMKDS
LKEMSLEEIYSYEKYGEFITQEGISFYNDICGKVNSFMNLYCQKNKENKNLYKLQKLHK
QILCIADTSYEVPYKFESDEEVYQSVNGFLDNISSKHIVERLRKIGDNYNGYNLDKIYIVS
KFYESVSQKTYRDWETINTALEIHYNNILPGNGKSKADKVKKAVKNDLQKSITEINELVS
NYKLCSDDNIKAETYIHEISHILNNFEAQELKYNPEIHLVESELKASELKNVLDVIMNAFH
WCSVFMTEELVDKDNNFYAELEEIYDEIYPVISLYNLVRNYVTQKPYSTKKIKLNFGIPT
LADGWSKSKEYSNNAIILMRDNLYYLGIFNAKNKPDKKIIEGNTSENKGDYKKMIYNLL
PGPNKMIPKVFLSSKTGVETYKPSAYILEGYKQNKHIKSSKDFDITFCHDLIDYFKNCIAI
HPEWKNFGFDFSDTSTYEDISGFYREVELQGYKIDWTYISEKDIDLLQEKGQLYLFQIYN
KDFSKKSTGNDNLHTMYLKNLFSEENLKDIVLKLNGEAEIFFRKSSIKNPIIHKKGSILVN
RTYEAEEKDQFGNIQIVRKNIPENIYQELYKYFNDKSDKELSDEAAKLKNVVGHHEAAT
NIVKDYRYTYDKYFLHMPITINFKANKTGFINDRILQYIAKEKDLHVIGIDRGERNLIYVS
VIDTCGNIVEQKSFNIVNGYDYQIKLKQQEGARQIARKEWKEIGHIKEIKEGYLSLVIHEI
SKMVIKYNAIIAMEDLSYGFKKGRFKVERQVYQKFETMLINKLNYLVFKDISITENGGLL
KGYQLTYIPDKLKNVGHQCGCIFYVPAAYTSKIDPTTGFVNIFKFKDLTVDAKREFIKKF
DSIRYDSEKNLFCFTFDYNNFITQNTVMSKSSWSVYTYGVRIKRRFVNGRFSNESDTIDIT
KDMEKTLEMTDINWRDGHDLRQDIIDYEIVQHIFEIFRLTVQMRNSLSELEDRDYDRLIS
PVLNENNIFYDSAKAGDALPKDADANGAYCIALKGLYEIKQITENWKEDGKFSRDKLKI
SNKDWFDFIQNKRYL*
SEQ ID NO: 43
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAACGGTACCAATAACTTCCAGAACTTCATCGGTATTTCTAGCCTGCAAAAGACCCT
GCGTAACGCGCTGATTCCGACCGAGACTACCCAGCAATTCATCGTGAAAAACGGTA
TCATTAAGGAAGATGAATTGCGCGGTGAGAATCGTCAGATTCTGAAAGATATCATG
GATGACTACTATCGCGGTTTCATTAGCGAAACCCTGTCGAGCATCGATGATATCGAT
TGGACGAGCCTCTTCGAGAAAATGGAAATTCAACTGAAAAATGGTGACAACAAAGA
TACCCTGATTAAAGAACAAACGGAATACCGCAAGGCAATCCATAAAAAGTTTGCGA
ATGACGACCGTTTTAAGAATATGTTCTCGGCCAAGCTGATTTCCGACATCCTGCCAG
AGTTCGTCATTCACAACAACAATTACAGCGCAAGCGAGAAAGAGGAAAAGACTCAG
GTCATTAAGCTGTTTAGCCGCTTTGCGACGTCCTTCAAAGACTACTTCAAGAATCGT
GCGAATTGCTTTAGCGCGGATGACATCTCTAGCTCTAGCTGTCACCGTATTGTTAAC
GACAATGCAGAGATTTTCTTCAGCAACGCCCTGGTGTATCGCCGTATTGTCAAGTCT
CTGAGCAACGACGACATTAACAAGATCAGCGGCGACATGAAAGACAGCCTGAAAG
AAATGTCTCTGGAAGAAATCTACAGCTACGAGAAATATGGTGAGTTTATCACCCAA
GAGGGCATTAGCTTCTACAATGATATCTGTGGTAAGGTTAATAGCTTTATGAATCTG
TACTGCCAGAAGAATAAAGAAAACAAGAACTTGTACAAGCTGCAAAAGCTGCATAA
GCAAATTCTGTGCATCGCCGATACTAGCTATGAAGTTCCGTACAAGTTCGAGTCTGA
TGAAGAGGTGTATCAGTCAGTCAACGGTTTTCTGGATAACATCAGCAGCAAGCACAT
CGTCGAGCGCCTGCGCAAGATTGGTGACAACTACAATGGTTATAACCTGGACAAGA
TCTATATCGTGTCGAAGTTTTACGAGAGCGTGTCCCAGAAAACGTACCGTGATTGGG
AAACGATTAACACGGCCTTGGAAATTCACTATAACAATATCCTGCCGGGCAACGGC
AAGAGCAAAGCTGACAAAGTCAAAAAAGCTGTGAAAAACGATCTGCAAAAGTCCAT
CACCGAGATCAACGAACTGGTTAGCAACTATAAGCTGTGTAGCGACGACAACATTA
AAGCTGAAACGTATATCCACGAAATCAGCCACATCCTGAATAACTTTGAGGCACAA
GAACTGAAATACAATCCTGAGATCCATCTGGTAGAGAGCGAGCTGAAGGCAAGCGA
GTTGAAAAACGTTCTCGACGTTATCATGAATGCTTTCCACTGGTGTAGCGTGTTTATG
ACCGAAGAACTGGTTGACAAAGATAACAATTTCTATGCAGAGCTGGAAGAAATCTA
TGATGAAATCTACCCGGTCATCAGCCTGTATAACCTGGTTCGTAACTACGTGACGCA
GAAGCCGTACAGCACCAAAAAGATCAAGCTGAACTTCGGTATTCCGACCTTGGCGG
ACGGTTGGAGCAAATCCAAAGAATACTCCAATAATGCGATTATTCTGATGCGTGATA
ATCTGTACTATCTGGGTATCTTCAATGCGAAGAACAAGCCAGATAAAAAGATTATTG
AAGGCAACACCAGCGAGAATAAAGGCGACTACAAGAAAATGATCTACAACTTATTG
CCGGGTCCGAACAAGATGATCCCGAAAGTTTTTCTGAGCAGCAAGACCGGCGTTGA
AACCTATAAGCCGAGCGCGTACATTTTAGAGGGCTATAAACAAAACAAGCACATCA
AGAGCAGCAAAGATTTTGATATTACGTTCTGCCACGACCTGATCGACTATTTCAAGA
ATTGTATTGCGATTCACCCTGAGTGGAAGAACTTCGGTTTTGACTTTTCCGATACCTC
CACCTATGAAGATATTAGCGGTTTTTACCGTGAAGTCGAGTTGCAGGGTTATAAGAT
TGATTGGACTTACATTTCCGAGAAAGACATCGACCTGTTGCAAGAGAAAGGTCAGCT
GTACCTGTTTCAGATCTATAACAAAGATTTCAGCAAAAAGTCGACGGGCAATGATA
ATCTGCACACCATGTATCTGAAAAACCTGTTTAGCGAAGAGAACCTGAAAGACATT
GTTCTTAAGCTGAATGGTGAGGCCGAGATCTTCTTCCGTAAAAGCTCCATTAAGAAC
CCGATTATCCACAAAAAGGGCTCTATTCTGGTTAACCGCACGTACGAAGCGGAAGA
GAAAGATCAATTTGGTAACATCCAGATCGTGCGTAAGAATATCCCGGAGAACATTT
ACCAAGAACTGTATAAGTATTTCAATGACAAGAGCGATAAAGAATTGAGCGATGAA
GCGGCAAAGCTGAAAAACGTCGTTGGCCACCACGAAGCCGCGACGAATATCGTGAA
AGATTATCGTTACACCTACGACAAGTACTTTCTGCACATGCCGATCACCATCAATTT
CAAAGCGAATAAAACGGGTTTTATCAATGACCGTATCCTGCAGTACATTGCGAAAG
AAAAAGATTTACACGTGATTGGTATTGATCGCGGCGAGCGCAATCTGATTTACGTCA
GCGTTATCGACACGTGCGGCAATATTGTGGAGCAGAAAAGCTTCAATATCGTCAATG
GTTACGACTACCAGATCAAACTGAAGCAACAAGAGGGCGCCCGCCAGATTGCGCGT
AAAGAGTGGAAAGAAATCGGTAAGATTAAAGAAATCAAGGAAGGCTACCTGTCCCT
GGTGATCCATGAAATCAGCAAAATGGTGATCAAGTACAACGCTATCATTGCGATGG
AAGATCTGAGCTACGGTTTTAAAAAGGGTCGCTTCAAAGTTGAGCGTCAAGTGTATC
AGAAATTTGAGACTATGCTGATTAACAAGTTGAACTATCTGGTTTTTAAAGACATCA
GCATTACCGAGAATGGTGGCCTGCTGAAGGGTTATCAACTGACCTATATTCCTGACA
AGTTGAAAAATGTTGGTCATCAGTGTGGTTGCATTTTCTACGTACCGGCAGCGTACA
CGAGCAAGATTGACCCGACCACGGGTTTCGTTAACATTTTCAAGTTTAAAGATTTGA
CCGTGGACGCCAAGCGTGAGTTCATTAAAAAGTTCGACAGCATCAGATACGACTCT
GAGAAGAATCTGTTCTGCTTTACGTTCGACTACAATAACTTCATTACCCAAAATACC
GTTATGAGCAAAAGCTCCTGGAGCGTGTACACGTACGGCGTCCGTATCAAGCGTCGT
TTTGTGAATGGTCGCTTTTCCAACGAATCTGACACCATTGACATTACCAAAGATATG
GAAAAGACCCTTGAGATGACCGACATTAATTGGCGTGATGGCCATGACTTGCGCCA
AGACATTATCGACTACGAAATTGTTCAGCACATCTTTGAGATTTTTCGTCTGACGGTC
CAGATGCGCAACTCGCTGAGCGAGTTGGAAGATCGTGACTATGACCGTCTGATTAGC
CCGGTGCTGAATGAAAACAATATCTTCTATGATAGCGCAAAGGCCGGTGACGCGCT
GCCGAAAGATGCGGATGCTAACGGTGCATACTGCATTGCACTGAAGGGTCTGTACG
AAATCAAACAGATCACCGAGAATTGGAAAGAGGATGGTAAGTTTAGCCGTGATAAG
CTGAAGATTAGCAATAAAGACTGGTTCGACTTTATTCAAAACAAGCGCTATCTGAAA
CGTCCGGCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTA
GCGGCGCAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACG
TAAGGTTATTCCGGGCTAA
SEQ ID NO: 44
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAACGGAACAAATAATTTTCAGAACTTTATTGGGATCAGTTCGCTTCAGAAAACGCT
TCGTAATGCTCTGATTCCCACAGAAACCACTCAGCAGTTTATCGTAAAGAATGGCAT
TATCAAGGAGGATGAATTACGCGGCGAGAACCGCCAAATCTTAAAAGATATCATGG
ACGACTACTACCGCGGTTTCATTAGCGAAACTCTTAGTTCAATTGACGACATTGACT
GGACGTCCTTGTTCGAAAAGATGGAGATTCAATTAAAGAACGGTGATAACAAGGAT
ACGTTGATTAAAGAACAGACGGAGTACCGTAAGGCTATCCACAAAAAATTTGCAAA
CGACGACCGCTTTAAAAATATGTTTAGCGCAAAATTAATCTCCGACATCCTGCCTGA
ATTCGTCATCCATAACAATAACTATAGCGCCTCGGAAAAAGAAGAAAAAACGCAGG
TTATTAAACTTTTCTCGCGCTTTGCAACAAGCTTTAAGGATTACTTCAAAAATCGCGC
CAATTGTTTTTCAGCCGACGACATTAGCTCCAGTTCCTGCCACCGTATTGTGAATGAC
AACGCTGAGATTTTTTTTTCCAATGCGCTGGTTTATCGTCGTATTGTTAAGAGCCTTA
GTAACGACGACATTAATAAAATTAGCGGTGATATGAAGGATAGCTTGAAAGAAATG
AGTCTGGAAGAGATCTATAGTTACGAGAAGTACGGCGAATTTATTACCCAGGAGGG
CATTTCATTTTACAATGATATCTGTGGAAAAGTCAACTCCTTTATGAACTTGTATTGC
CAAAAGAATAAAGAAAACAAAAACCTGTACAAACTGCAAAAGTTACACAAGCAGA
TTTTGTGTATCGCAGACACGTCATACGAAGTACCGTACAAGTTTGAGTCCGATGAAG
AAGTGTACCAAAGCGTTAATGGCTTTTTGGATAACATTTCGAGCAAACATATCGTAG
AGCGTTTGCGTAAGATTGGTGATAATTACAACGGTTACAATTTAGACAAAATCTATA
TCGTCTCTAAGTTTTACGAAAGTGTTTCTCAGAAAACTTACCGCGATTGGGAGACGA
TCAACACTGCGCTGGAGATTCATTACAATAATATCCTTCCAGGTAACGGTAAAAGCA
AAGCTGATAAGGTGAAAAAGGCGGTTAAAAATGACCTTCAAAAGTCTATCACAGAA
ATCAACGAATTGGTCAGCAATTATAAGCTTTGCAGTGACGATAACATTAAGGCCGA
GACTTACATCCATGAGATCTCTCACATTCTTAATAATTTTGAAGCGCAAGAGCTGAA
ATACAATCCTGAAATCCATCTGGTCGAAAGTGAATTAAAAGCCTCCGAATTAAAAA
ATGTCTTGGACGTGATCATGAATGCGTTCCATTGGTGCTCAGTTTTTATGACGGAAG
AGTTGGTGGACAAAGACAACAATTTTTACGCCGAGCTTGAGGAAATTTACGACGAA
ATTTACCCCGTTATTTCGTTATACAACCTTGTGCGTAATTACGTTACACAAAAGCCCT
ATTCGACAAAGAAAATCAAGTTAAATTTCGGGATTCCCACATTAGCTGATGGATGGT
CCAAATCCAAAGAATACTCGAATAACGCTATCATCCTTATGCGTGATAATTTGTACT
ACTTAGGCATCTTCAATGCGAAGAACAAACCTGACAAGAAAATTATCGAAGGAAAC
ACTTCGGAGAACAAAGGTGATTATAAAAAGATGATCTACAACTTGCTTCCCGGGCC
AAACAAAATGATTCCCAAGGTATTTTTGAGTTCTAAAACCGGTGTCGAAACTTACAA
ACCAAGTGCTTATATTTTGGAAGGATACAAACAGAACAAACATATCAAGTCTTCGA
AAGACTTCGATATTACGTTCTGCCACGATCTGATCGATTACTTCAAGAACTGTATTG
CTATTCACCCCGAGTGGAAGAACTTTGGATTTGATTTCTCCGACACGTCCACTTATG
AAGATATCTCTGGCTTCTATCGCGAGGTTGAATTACAAGGGTATAAGATTGACTGGA
CTTATATTTCGGAGAAGGATATCGATCTTTTGCAAGAAAAAGGGCAACTTTATTTAT
TTCAGATCTATAACAAGGACTTTTCAAAAAAGAGCACTGGAAATGACAATCTGCAT
ACCATGTACCTTAAGAACCTGTTCTCGGAAGAGAACCTGAAGGACATTGTACTTAAA
CTGAATGGAGAGGCAGAGATCTTCTTTCGCAAATCAAGCATTAAGAACCCAATTATT
CACAAAAAGGGGAGTATCTTAGTAAATCGCACATATGAGGCTGAGGAAAAAGATCA
GTTTGGTAACATTCAGATCGTGCGTAAGAACATTCCTGAAAATATCTATCAGGAACT
TTATAAGTATTTCAACGATAAAAGTGATAAAGAGCTGAGTGACGAAGCGGCTAAAC
TTAAGAATGTTGTGGGACACCATGAGGCAGCAACCAATATTGTGAAGGATTATCGCT
ATACGTACGACAAATACTTTTTACACATGCCCATCACTATTAATTTTAAAGCTAATA
AGACTGGCTTCATTAACGATCGCATCCTGCAGTACATTGCTAAGGAAAAGGATCTTC
ACGTTATCGGTATCGATCGCGGGGAGCGTAATCTTATCTACGTCTCTGTCATTGACA
CGTGTGGCAATATTGTGGAGCAAAAGTCCTTCAATATTGTTAACGGCTATGACTATC
AGATTAAATTGAAACAGCAGGAAGGTGCGCGTCAGATTGCCCGCAAGGAATGGAAG
GAAATTGGCAAGATCAAAGAAATTAAGGAGGGCTACTTAAGCTTAGTAATTCACGA
AATTAGTAAAATGGTTATCAAATACAACGCCATCATCGCGATGGAGGATCTTTCGTA
CGGGTTTAAGAAAGGTCGTTTTAAAGTGGAGCGTCAGGTGTACCAGAAATTTGAAA
CTATGCTTATTAACAAACTTAACTACCTGGTTTTCAAGGATATCAGTATTACTGAAA
ACGGGGGGCTGTTAAAAGGGTATCAATTAACTTACATTCCAGACAAATTAAAGAAC
GTTGGACATCAGTGTGGCTGCATTTTTTATGTACCAGCTGCATACACTTCAAAGATC
GATCCTACGACTGGGTTCGTGAACATTTTTAAGTTTAAAGACTTGACGGTAGATGCC
AAGCGCGAATTCATCAAGAAATTCGACAGCATTCGCTACGACTCTGAGAAAAATCTT
TTCTGTTTCACATTCGATTATAACAATTTCATTACGCAGAACACAGTAATGTCCAAGT
CTTCTTGGAGTGTTTATACATATGGTGTCCGCATTAAGCGCCGTTTCGTCAACGGCCG
CTTCAGTAATGAGAGCGATACTATTGACATCACAAAAGACATGGAAAAAACACTGG
AAATGACCGACATCAATTGGCGTGACGGCCATGACTTACGTCAGGATATCATTGATT
ATGAGATCGTTCAACACATCTTCGAAATCTTTCGCTTGACTGTTCAAATGCGCAATTC
CTTGTCGGAATTGGAGGACCGTGATTATGACCGCTTAATTTCCCCCGTCTTAAATGA
AAACAATATTTTTTATGACTCTGCAAAAGCTGGAGATGCTCTGCCGAAAGACGCCGA
TGCAAATGGGGCATATTGCATTGCTTTAAAGGGGCTTTACGAGATCAAGCAAATCAC
CGAAAACTGGAAAGAGGATGGAAAGTTTTCGCGTGATAAACTGAAGATCTCTAACA
AAGACTGGTTCGACTTTATCCAGAACAAGCGTTATTTGAAACGTCCGGCAGCGACCA
AAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCC
GAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCT
AA
SEQ ID NO: 45
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAACGGCACCAATAACTTCCAAAACTTCATCGGGATCTCTAGCCTTCAGAAGACGCT
TCGCAATGCTCTTATCCCAACTGAGACCACTCAACAATTTATTGTGAAGAATGGAAT
TATTAAAGAGGACGAACTGCGTGGCGAGAATCGTCAGATCTTAAAGGACATTATGG
ATGATTATTACCGTGGATTCATCTCCGAAACATTATCGTCGATCGATGATATCGATT
GGACTTCTCTGTTCGAGAAAATGGAAATTCAATTGAAAAACGGAGATAATAAAGAT
ACGCTTATCAAAGAACAGACGGAATATCGTAAAGCGATTCATAAGAAATTCGCAAA
TGACGATCGTTTCAAAAATATGTTCAGTGCCAAGCTTATTTCGGACATTTTACCTGA
ATTTGTAATTCATAATAATAACTACTCAGCAAGTGAGAAGGAGGAGAAAACCCAAG
TTATTAAACTGTTCTCTCGTTTCGCAACGTCCTTTAAAGATTACTTTAAAAACCGCGC
GAATTGCTTTAGCGCTGACGACATTTCCAGCTCATCCTGTCATCGCATCGTAAACGA
CAATGCGGAAATCTTCTTCAGCAACGCCCTGGTTTACCGCCGCATCGTCAAAAGCTT
ATCGAATGACGACATCAATAAGATCTCAGGAGATATGAAGGACTCGCTTAAGGAGA
TGTCTCTGGAGGAAATTTATAGTTACGAAAAGTATGGAGAGTTCATTACCCAGGAGG
GAATCTCGTTCTACAATGACATTTGCGGGAAGGTGAACTCCTTCATGAACTTATACT
GCCAGAAAAACAAAGAGAACAAAAATCTGTATAAATTGCAGAAATTACATAAACAG
ATTCTTTGTATTGCTGACACTTCCTACGAAGTACCCTATAAATTCGAGTCAGATGAA
GAAGTATACCAGTCCGTGAACGGATTTCTGGACAATATCTCCTCAAAACACATCGTG
GAACGCTTACGTAAAATTGGCGATAATTATAATGGTTACAATCTTGACAAAATTTAT
ATCGTATCTAAATTTTACGAGAGTGTGAGCCAAAAGACCTACCGCGACTGGGAGAC
CATCAACACAGCTTTAGAAATTCACTATAATAATATCTTACCCGGCAATGGTAAGAG
CAAGGCTGACAAGGTAAAAAAGGCCGTCAAGAATGATTTGCAGAAATCTATTACAG
AAATTAATGAGTTAGTCTCCAACTATAAGCTTTGTTCCGACGATAACATCAAAGCTG
AGACATATATTCATGAGATTAGTCACATTCTTAACAACTTCGAGGCCCAGGAACTTA
AGTACAATCCTGAAATTCATCTTGTCGAGTCTGAGCTGAAAGCTAGTGAATTGAAAA
ATGTTTTAGACGTTATTATGAACGCATTCCACTGGTGCTCTGTGTTTATGACAGAAG
AACTGGTCGACAAGGACAATAACTTCTATGCCGAACTTGAGGAAATCTACGATGAA
ATTTACCCTGTAATCTCCTTGTATAATCTTGTACGTAATTACGTCACTCAAAAACCTT
ACAGCACGAAAAAAATTAAATTGAACTTCGGGATTCCTACACTTGCCGACGGGTGG
TCTAAATCCAAGGAATATAGCAACAATGCCATTATTTTAATGCGCGACAATCTTTAC
TATTTAGGAATTTTTAACGCTAAGAACAAGCCCGATAAAAAGATTATTGAAGGAAA
CACGTCTGAAAATAAGGGCGACTACAAAAAGATGATTTATAACCTTTTGCCCGGTCC
AAACAAAATGATCCCAAAGGTATTCCTGTCATCCAAAACAGGGGTTGAGACATATA
AGCCCAGCGCATATATTCTGGAAGGATACAAACAGAATAAACATATCAAAAGCAGC
AAAGATTTTGACATTACTTTTTGCCACGATTTAATCGACTACTTCAAAAACTGTATCG
CTATCCACCCTGAATGGAAGAATTTCGGATTTGATTTCTCAGATACAAGTACGTATG
AGGATATCAGCGGTTTCTATCGCGAAGTTGAACTTCAAGGGTATAAAATTGACTGGA
CCTACATTAGTGAGAAGGACATCGACCTGTTACAGGAAAAAGGCCAATTGTACTTGT
TTCAGATCTACAATAAGGATTTCTCAAAAAAATCGACCGGCAATGATAACTTGCACA
CCATGTACCTGAAGAACCTTTTTTCGGAGGAAAACCTTAAAGACATTGTCCTGAAGT
TGAATGGAGAAGCGGAGATTTTCTTTCGTAAGTCTTCCATTAAAAATCCAATTATTC
ATAAGAAGGGCAGCATCCTTGTGAACCGTACGTACGAGGCGGAAGAGAAGGACCA
ATTCGGTAACATTCAAATCGTCCGCAAGAACATCCCTGAAAATATTTATCAGGAGCT
TTACAAGTATTTCAATGATAAGTCCGACAAGGAATTATCAGATGAGGCTGCGAAGTT
GAAAAATGTTGTTGGTCATCACGAGGCGGCGACGAATATTGTAAAGGATTATCGCT
ACACTTATGACAAGTACTTTCTGCACATGCCGATCACCATTAATTTCAAGGCGAACA
AAACAGGATTTATTAATGACCGCATCTTACAATACATTGCCAAAGAAAAGGACTTAC
ACGTTATTGGCATTGATCGTGGAGAACGCAACTTAATCTACGTAAGCGTTATTGACA
CTTGCGGGAATATCGTAGAACAAAAGAGCTTCAACATCGTGAATGGTTACGATTACC
AGATCAAGCTTAAGCAGCAGGAGGGAGCGCGCCAGATCGCGCGCAAGGAATGGAA
GGAGATTGGTAAGATCAAGGAAATCAAGGAAGGTTATCTGTCCTTGGTAATCCACG
AAATTTCGAAAATGGTTATCAAATACAATGCTATTATTGCAATGGAGGACTTGTCCT
ACGGCTTTAAAAAAGGACGCTTTAAGGTGGAGCGCCAGGTTTATCAAAAGTTTGAA
ACAATGCTGATTAACAAGCTGAACTATTTGGTCTTTAAAGATATCTCCATCACCGAA
AATGGTGGGCTTTTGAAAGGCTATCAACTTACATATATCCCTGATAAGCTTAAGAAT
GTGGGTCATCAGTGCGGGTGCATTTTTTATGTTCCTGCAGCCTACACGTCCAAAATC
GATCCTACAACTGGATTTGTTAATATCTTCAAATTTAAGGATCTTACCGTCGACGCG
AAGCGCGAATTTATCAAGAAATTCGATAGTATTCGTTATGATTCCGAAAAAAACCTT
TTCTGTTTCACCTTTGATTATAATAACTTTATCACGCAAAATACTGTCATGAGCAAAT
CGAGTTGGTCTGTGTACACTTACGGAGTACGCATCAAGCGTCGTTTTGTTAATGGGC
GCTTCAGTAACGAGTCAGACACGATTGATATCACAAAAGATATGGAGAAAACGCTG
GAGATGACAGACATCAATTGGCGCGATGGTCATGACTTACGTCAAGACATTATCGAT
TATGAAATTGTCCAGCATATCTTTGAGATCTTTCGTTTGACTGTTCAGATGCGCAACA
GCCTGTCAGAATTGGAGGATCGTGACTATGATCGCCTTATTTCTCCCGTCTTAAATG
AGAACAATATCTTCTACGACTCAGCCAAGGCTGGAGATGCACTGCCAAAAGACGCC
GACGCAAATGGGGCCTACTGTATTGCATTGAAGGGGTTGTACGAGATCAAACAGAT
TACAGAAAATTGGAAGGAGGACGGTAAGTTCTCTCGTGATAAGCTGAAGATTTCTA
ACAAAGACTGGTTCGATTTCATTCAGAACAAACGTTACCTGAAACGTCCGGCAGCG
ACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCA
GCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCG
GGCTAA
SEQ ID NO: 46
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAACGGTACCAATAACTTTCAGAATTTCATTGGAATCAGCAGCTTACAGAAAACCCT
GCGCAATGCACTTATCCCCACTGAGACAACCCAGCAGTTCATTGTAAAGAACGGGA
TTATTAAAGAAGATGAGCTTCGCGGGGAGAATCGTCAGATCTTAAAGGATATTATG
GACGATTACTACCGTGGCTTCATTTCGGAGACGCTGTCGTCGATCGACGACATCGAC
TGGACATCCTTGTTTGAAAAGATGGAAATCCAACTGAAGAATGGCGATAACAAGGA
CACGTTAATCAAAGAGCAGACGGAATACCGTAAAGCTATCCACAAAAAGTTCGCTA
ATGACGACCGCTTTAAGAACATGTTCTCAGCAAAACTTATTAGCGATATTTTACCTG
AATTTGTCATCCACAATAACAATTACTCCGCGAGTGAAAAAGAGGAGAAAACCCAG
GTGATTAAGCTGTTTTCCCGTTTTGCAACCAGTTTCAAGGACTATTTTAAGAATCGTG
CTAATTGTTTCTCTGCAGACGACATTTCCTCGTCGTCCTGCCATCGCATTGTTAATGA
TAATGCTGAAATCTTTTTTTCAAACGCACTTGTGTATCGTCGCATTGTCAAAAGCTTA
AGTAATGACGATATCAATAAGATCTCAGGAGACATGAAGGACTCCCTGAAAGAAAT
GTCATTGGAAGAAATTTACTCTTATGAAAAGTATGGAGAATTTATTACGCAGGAGGG
TATCAGCTTCTATAACGACATTTGTGGTAAAGTGAACAGCTTTATGAATCTTTATTGT
CAAAAGAATAAAGAGAACAAAAATCTGTACAAGCTGCAGAAATTGCATAAACAAAT
TCTGTGCATTGCAGATACTTCGTATGAGGTTCCTTACAAATTCGAGTCGGATGAGGA
GGTGTATCAAAGCGTAAACGGATTTTTGGATAACATTAGTAGTAAGCATATTGTGGA
ACGCCTTCGCAAGATTGGTGACAACTATAACGGATACAACTTAGACAAGATCTATAT
TGTCTCGAAGTTTTACGAAAGTGTTTCCCAAAAGACTTATCGCGACTGGGAGACAAT
CAACACTGCGCTGGAAATTCACTATAACAATATCTTGCCGGGGAACGGAAAAAGTA
AGGCAGATAAGGTGAAGAAAGCAGTCAAAAATGATCTGCAAAAAAGCATTACTGA
AATTAACGAACTTGTGTCAAATTACAAATTGTGTTCGGATGACAATATTAAAGCGGA
AACGTATATCCACGAGATCTCGCACATTCTTAATAATTTCGAGGCGCAGGAATTAAA
GTATAATCCTGAGATCCATTTGGTGGAATCAGAACTTAAAGCTAGTGAACTGAAAA
ATGTCCTGGACGTTATTATGAATGCATTTCACTGGTGTTCTGTCTTTATGACAGAAGA
ACTTGTCGACAAAGACAACAACTTTTATGCGGAATTAGAAGAGATTTACGACGAAA
TTTATCCCGTTATTTCGTTATATAATTTAGTTCGTAATTACGTGACTCAGAAACCCTA
CAGCACAAAAAAGATTAAATTAAACTTTGGGATTCCGACTCTTGCTGATGGATGGAG
CAAGTCCAAGGAGTACTCTAATAACGCCATTATCTTGATGCGTGACAACCTGTACTA
CCTGGGCATTTTTAACGCTAAAAACAAACCCGACAAAAAGATCATTGAAGGGAACA
CCTCGGAAAATAAGGGGGACTATAAAAAAATGATCTACAATCTGTTGCCAGGCCCA
AATAAGATGATCCCAAAGGTTTTTTTATCTTCCAAAACTGGCGTAGAAACTTACAAG
CCGAGCGCATACATCCTTGAAGGATATAAACAAAACAAACATATCAAAAGTTCAAA
GGACTTCGATATTACGTTCTGCCATGATTTAATCGATTATTTCAAGAATTGCATCGCG
ATTCACCCAGAGTGGAAAAACTTTGGGTTTGATTTTTCAGACACCAGCACTTACGAG
GATATTAGTGGATTCTATCGTGAGGTTGAACTGCAGGGCTATAAAATTGACTGGACC
TATATTTCTGAAAAAGATATTGATCTGCTTCAGGAGAAAGGCCAATTGTACTTATTT
CAAATCTATAACAAGGATTTCTCCAAGAAGTCCACGGGTAATGACAACTTACACAC
AATGTATCTGAAGAATCTGTTTAGTGAGGAGAACTTGAAGGACATTGTGCTGAAGCT
TAATGGCGAGGCCGAAATCTTTTTTCGTAAGTCCTCCATTAAAAACCCTATTATCCAT
AAGAAAGGGAGTATTCTTGTCAACCGCACGTATGAGGCCGAAGAAAAGGACCAATT
CGGAAACATCCAAATTGTCCGTAAAAATATTCCTGAGAACATTTACCAGGAGCTTTA
CAAGTATTTCAACGACAAGAGTGATAAAGAACTTTCAGATGAGGCGGCGAAACTGA
AGAATGTAGTGGGGCACCACGAAGCTGCCACGAATATTGTAAAGGATTACCGTTAC
ACCTACGACAAGTACTTTTTGCATATGCCCATCACAATTAATTTTAAGGCCAATAAA
ACTGGTTTTATCAACGATCGTATCTTACAGTACATTGCTAAGGAAAAAGATCTGCAC
GTTATCGGTATCGATCGCGGGGAACGCAATCTGATTTATGTTAGTGTGATTGACACG
TGCGGAAATATTGTTGAGCAGAAGAGCTTTAATATCGTAAATGGATATGACTATCAA
ATTAAACTGAAGCAACAGGAAGGGGCCCGCCAGATTGCCCGCAAGGAGTGGAAAG
AAATTGGAAAGATCAAGGAGATTAAAGAAGGGTACCTTTCCCTTGTTATCCACGAA
ATCTCGAAAATGGTGATCAAGTACAATGCCATTATTGCTATGGAGGATCTGTCATAT
GGGTTTAAGAAAGGCCGCTTTAAGGTGGAACGTCAGGTTTACCAGAAGTTTGAGAC
CATGCTTATCAATAAGCTGAATTATCTTGTCTTCAAAGACATCTCAATCACAGAGAA
CGGCGGGCTGTTAAAAGGATATCAGCTGACCTATATCCCCGACAAACTGAAAAATG
TCGGGCACCAATGCGGCTGTATTTTCTACGTGCCCGCTGCATACACATCTAAAATTG
ACCCAACGACTGGATTCGTAAATATTTTTAAGTTTAAGGATCTTACGGTAGATGCAA
AGCGCGAATTTATCAAGAAATTTGATAGTATCCGTTACGACAGCGAGAAAAACTTAT
TTTGTTTTACGTTCGATTATAACAACTTCATCACGCAAAATACCGTCATGTCAAAATC
TTCCTGGTCAGTCTATACGTATGGCGTCCGTATCAAGCGCCGCTTCGTCAACGGGCG
TTTTTCAAACGAGTCAGATACCATCGATATCACCAAAGATATGGAAAAAACATTGG
AGATGACGGACATCAATTGGCGCGATGGTCATGACTTACGCCAGGACATTATTGACT
ACGAAATCGTACAACATATTTTTGAGATTTTCCGTCTGACCGTGCAAATGCGCAACT
CATTATCCGAACTTGAGGATCGTGATTACGACCGCTTGATCAGTCCTGTTCTGAACG
AGAATAATATTTTTTACGACAGTGCCAAGGCGGGAGACGCACTGCCCAAGGACGCT
GACGCTAACGGAGCTTATTGTATTGCGTTGAAGGGACTTTACGAAATCAAGCAAATC
ACTGAAAACTGGAAGGAGGATGGTAAATTCTCACGCGACAAGTTGAAAATTTCGAA
CAAGGACTGGTTCGATTTCATCCAAAACAAGCGTTATTTAAAACGTCCGGCAGCGAC
CAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGC
CCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGG
GCTAA
SEQ ID NO: 47
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAACGGGACTAATAACTTCCAGAACTTCATCGGTATTTCATCATTACAAAAAACGCT
TCGTAACGCCTTGATCCCAACAGAAACGACCCAACAATTTATTGTAAAAAACGGCAT
CATCAAAGAAGACGAACTGCGTGGCGAAAATCGCCAAATTTTGAAGGACATTATGG
ATGACTATTATCGTGGGTTTATCTCGGAGACATTATCCTCCATCGACGACATTGATTG
GACGAGTCTTTTTGAGAAAATGGAGATCCAGCTTAAAAATGGTGATAACAAGGATA
CATTGATCAAGGAGCAAACCGAGTACCGCAAGGCCATCCATAAGAAGTTCGCAAAT
GACGACCGCTTCAAAAATATGTTTAGTGCCAAATTGATCTCGGATATCCTTCCTGAG
TTCGTAATTCACAACAATAATTATAGCGCATCCGAAAAGGAGGAAAAGACTCAAGT
CATTAAGCTTTTCAGTCGCTTTGCTACCTCGTTTAAGGACTATTTCAAGAACCGCGCG
AACTGCTTCTCAGCGGATGACATTTCTTCCTCGTCGTGTCACCGCATCGTGAATGATA
ATGCGGAGATCTTCTTTAGTAATGCCTTGGTATACCGCCGCATTGTTAAATCCCTGTC
TAACGACGATATCAATAAGATCTCAGGAGATATGAAGGATAGCCTTAAAGAAATGT
CTCTGGAAGAAATTTACTCCTATGAAAAGTACGGTGAGTTTATCACCCAAGAGGGG
ATTAGCTTTTATAACGATATCTGCGGGAAGGTGAATTCGTTTATGAACCTTTATTGTC
AAAAGAATAAGGAGAATAAGAACTTATATAAGCTTCAGAAACTGCATAAACAAATC
TTATGCATTGCCGATACTAGCTATGAAGTTCCGTATAAATTCGAGAGCGATGAAGAA
GTTTATCAGAGCGTCAATGGGTTCTTGGATAACATTTCATCAAAACACATCGTGGAA
CGTCTGCGTAAGATTGGGGATAACTACAACGGATATAATCTTGACAAAATTTATATT
GTATCTAAATTCTATGAGTCGGTGAGTCAAAAGACCTACCGTGATTGGGAAACAATC
AATACCGCGTTAGAAATCCACTATAACAACATTCTGCCAGGGAATGGTAAAAGTAA
AGCGGACAAAGTCAAGAAGGCTGTGAAGAACGATCTGCAAAAGAGTATTACAGAG
ATTAACGAATTAGTCTCCAATTATAAGTTATGCTCGGACGATAACATTAAGGCGGAG
ACGTATATTCATGAGATTTCGCATATTCTTAACAACTTCGAGGCACAAGAGCTTAAG
TATAACCCAGAGATTCACCTTGTCGAATCGGAGCTGAAGGCATCGGAATTAAAAAA
TGTCTTAGATGTAATCATGAACGCGTTCCATTGGTGCAGTGTTTTCATGACTGAGGA
GTTAGTTGACAAGGACAATAACTTCTACGCAGAATTAGAAGAGATCTATGATGAGA
TTTATCCAGTGATTTCGCTGTATAATCTGGTACGTAATTACGTCACTCAAAAGCCCTA
CTCAACAAAAAAAATTAAGCTGAACTTCGGAATTCCGACTCTGGCCGACGGGTGGT
CCAAGTCAAAGGAGTATTCTAATAATGCTATCATCCTGATGCGCGATAACTTATACT
ATTTGGGAATTTTCAATGCCAAAAATAAACCAGATAAAAAGATTATCGAAGGTAAT
ACAAGCGAGAATAAGGGTGACTATAAGAAAATGATTTACAATCTTCTTCCAGGCCCT
AACAAGATGATTCCCAAAGTTTTTTTGTCCAGTAAAACAGGGGTCGAAACTTACAAG
CCCAGTGCCTATATCCTTGAAGGGTACAAGCAGAATAAGCACATCAAATCCTCGAA
AGACTTTGATATTACATTTTGTCATGACTTAATCGATTATTTTAAGAACTGTATCGCA
ATCCATCCAGAATGGAAGAACTTCGGGTTTGATTTCTCTGATACTTCCACGTATGAG
GATATTTCCGGGTTCTACCGCGAAGTAGAGCTTCAGGGCTATAAAATTGACTGGACA
TATATTTCAGAAAAAGACATCGATCTGTTACAAGAAAAAGGACAGTTGTATCTGTTT
CAAATCTATAATAAGGATTTCTCCAAAAAGTCAACTGGAAATGATAACTTACATACA
ATGTATCTGAAAAATCTTTTTAGTGAAGAGAATTTGAAGGATATCGTGCTGAAGTTA
AATGGCGAAGCAGAGATCTTCTTCCGCAAGTCCTCGATCAAGAATCCTATCATCCAC
AAGAAAGGTAGTATTCTGGTTAACCGCACGTACGAGGCCGAGGAAAAAGACCAGTT
CGGTAATATCCAGATTGTACGTAAGAATATTCCTGAAAATATTTACCAGGAATTATA
CAAGTATTTTAACGACAAATCGGATAAGGAGCTTTCAGATGAGGCCGCAAAGTTGA
AGAACGTCGTAGGACACCATGAGGCCGCTACGAATATCGTCAAGGACTACCGCTAT
ACGTATGACAAGTACTTCCTGCACATGCCTATTACTATCAATTTCAAAGCTAATAAA
ACAGGATTCATCAATGATCGTATCCTTCAGTACATTGCCAAAGAAAAAGATCTGCAC
GTAATCGGAATCGACCGTGGCGAACGTAATCTGATTTACGTATCAGTTATCGACACA
TGTGGTAACATCGTGGAGCAGAAATCTTTTAACATTGTTAACGGCTATGATTATCAG
ATTAAGCTTAAACAGCAGGAGGGGGCACGCCAAATCGCTCGTAAAGAATGGAAGGA
GATTGGAAAGATTAAAGAGATTAAAGAGGGGTACCTTTCGCTGGTTATTCACGAAA
TTTCCAAGATGGTGATTAAGTACAATGCAATCATCGCGATGGAAGATCTTAGTTACG
GATTCAAAAAGGGACGCTTCAAAGTTGAGCGTCAGGTCTACCAGAAATTTGAAACG
ATGCTGATTAACAAATTGAATTACTTGGTATTCAAAGATATCTCAATTACTGAAAAT
GGTGGCTTATTAAAGGGTTACCAGCTTACCTATATCCCGGATAAGCTGAAGAACGTG
GGCCATCAATGCGGCTGCATCTTTTACGTCCCTGCCGCATATACCTCTAAAATTGAC
CCCACCACCGGATTCGTAAATATTTTTAAATTCAAGGACCTGACGGTGGACGCCAAG
CGCGAATTCATCAAAAAATTCGACTCAATCCGCTATGATTCCGAAAAAAATCTTTTC
TGCTTTACGTTCGATTATAATAACTTCATTACCCAAAACACGGTGATGTCAAAATCG
TCCTGGAGCGTGTATACTTATGGAGTGCGTATCAAGCGCCGCTTTGTTAATGGGCGC
TTCAGTAACGAAAGCGATACCATCGACATTACCAAAGACATGGAGAAGACGCTTGA
AATGACGGATATCAATTGGCGTGACGGACACGATCTTCGTCAGGATATCATCGACTA
CGAGATTGTGCAACATATCTTTGAGATTTTCCGTTTAACTGTTCAAATGCGTAACTCC
TTGTCCGAATTGGAAGACCGTGATTACGACCGCTTGATTTCACCAGTGCTTAACGAG
AATAACATCTTCTACGACTCCGCCAAAGCAGGCGATGCCCTGCCAAAGGACGCTGA
TGCAAATGGTGCATACTGTATCGCGTTGAAGGGCTTATACGAGATTAAGCAAATCAC
CGAAAATTGGAAAGAGGATGGAAAGTTCAGTCGCGATAAGCTGAAGATCTCTAATA
AAGATTGGTTTGACTTTATCCAGAACAAACGTTATTTAAAACGTCCGGCAGCGACCA
AAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCC
GAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCT
AA
SEQ ID NO: 48
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAACGGTACCAATAATTTCCAAAATTTCATCGGAATCTCATCCTTGCAAAAAACCTT
GCGCAATGCTTTGATCCCCACCGAAACCACGCAGCAGTTCATCGTGAAAAACGGCA
TTATCAAAGAGGATGAGTTGCGCGGGGAAAACCGTCAAATTCTTAAGGATATCATG
GACGATTACTACCGTGGGTTTATCAGTGAGACCCTGTCAAGCATTGACGACATTGAC
TGGACCAGCTTATTTGAGAAGATGGAGATTCAATTAAAGAACGGGGACAATAAGGA
CACGCTTATCAAAGAGCAGACAGAATACCGTAAAGCGATTCATAAGAAATTTGCAA
ATGACGATCGCTTCAAGAACATGTTTTCAGCAAAATTAATCAGCGACATCCTTCCCG
AATTTGTGATTCATAATAACAACTATTCGGCTAGCGAAAAAGAGGAGAAAACTCAG
GTTATTAAGCTTTTCTCGCGTTTTGCCACTTCGTTCAAAGACTATTTTAAGAATCGCG
CAAACTGCTTTTCGGCTGATGATATTTCCAGTTCTAGCTGCCATCGTATCGTTAACGA
TAATGCTGAGATTTTCTTCTCTAATGCCCTGGTGTATCGTCGTATCGTTAAATCTTTG
AGCAACGACGATATTAATAAGATTTCAGGCGACATGAAGGATTCTTTAAAGGAGAT
GTCTTTAGAAGAGATTTATTCCTATGAGAAATATGGCGAGTTTATCACCCAAGAAGG
AATTTCGTTCTACAACGACATCTGTGGCAAAGTGAACAGCTTCATGAATTTATACTG
CCAAAAGAATAAGGAGAATAAAAATTTATATAAACTGCAGAAACTGCATAAGCAAA
TTCTTTGCATTGCAGACACCTCTTATGAAGTTCCTTATAAGTTTGAATCGGACGAGG
AGGTATATCAGAGTGTGAACGGGTTCCTGGACAATATTTCATCCAAGCATATTGTTG
AACGTTTACGCAAAATTGGAGACAATTACAATGGGTATAACCTTGACAAAATTTACA
TCGTGTCGAAGTTTTACGAATCGGTAAGCCAGAAGACCTATCGTGACTGGGAAACTA
TCAATACCGCCTTAGAAATTCATTACAACAATATTCTTCCTGGTAACGGCAAAAGCA
AAGCCGATAAGGTAAAGAAGGCTGTCAAGAACGACCTGCAAAAGTCTATCACAGAG
ATCAACGAGTTAGTCTCTAACTACAAATTATGTTCCGACGACAATATTAAAGCCGAA
ACCTACATCCATGAGATCTCACACATTCTTAACAATTTTGAGGCCCAGGAGCTGAAA
TATAACCCAGAAATTCACCTTGTAGAGAGCGAATTAAAAGCCTCCGAGCTGAAGAA
CGTTTTGGATGTAATCATGAACGCATTTCATTGGTGCAGCGTATTTATGACAGAGGA
GTTGGTCGACAAGGACAATAACTTTTACGCCGAGCTTGAAGAAATCTACGATGAAA
TTTACCCGGTAATTAGTTTATATAATTTAGTTCGCAACTACGTAACTCAGAAACCCTA
CAGTACCAAGAAGATTAAATTGAACTTTGGGATCCCGACACTTGCTGACGGTTGGAG
TAAATCAAAAGAATACTCCAATAATGCAATTATCCTGATGCGCGACAATCTTTACTA
CTTGGGGATCTTTAACGCAAAGAACAAACCAGATAAGAAAATCATCGAGGGCAACA
CCAGCGAGAATAAAGGCGATTACAAGAAAATGATCTATAATCTTTTGCCGGGACCG
AACAAAATGATCCCAAAGGTTTTCCTGTCGTCGAAAACGGGAGTCGAGACATATAA
ACCATCTGCGTACATCTTGGAAGGTTACAAACAGAATAAGCATATTAAGTCTAGTAA
AGACTTCGACATCACCTTTTGTCATGACCTGATTGATTATTTCAAGAACTGTATTGCT
ATCCATCCAGAATGGAAAAACTTCGGATTTGACTTCTCCGATACTAGCACCTACGAA
GACATTTCGGGTTTTTATCGCGAAGTAGAGCTTCAAGGGTACAAAATTGATTGGACA
TATATTAGCGAGAAAGACATTGATTTGCTTCAAGAGAAGGGACAGTTATATTTATTC
CAGATCTACAACAAAGACTTCTCGAAGAAATCCACCGGTAATGATAATCTTCACACT
ATGTACCTGAAGAATTTATTTTCAGAGGAAAATCTGAAGGACATTGTACTTAAACTT
AATGGAGAAGCCGAAATCTTCTTCCGCAAGAGTTCCATTAAAAATCCGATTATTCAT
AAAAAGGGAAGTATCCTTGTGAACCGCACGTATGAGGCCGAAGAGAAGGATCAGTT
TGGGAATATTCAAATTGTCCGCAAAAACATCCCCGAGAACATCTACCAGGAACTGT
ATAAATACTTTAATGATAAATCTGATAAAGAGTTATCAGACGAGGCTGCCAAACTG
AAAAACGTAGTCGGTCATCATGAGGCAGCGACCAATATTGTAAAGGACTACCGTTA
CACCTACGACAAGTATTTCCTTCACATGCCGATCACGATTAATTTTAAGGCTAACAA
GACCGGCTTTATCAATGACCGCATCTTGCAGTACATCGCGAAAGAGAAAGATTTACA
CGTCATCGGAATTGATCGTGGAGAGCGTAATCTTATCTACGTCAGCGTCATCGACAC
CTGTGGAAACATTGTGGAACAAAAAAGTTTTAATATCGTAAACGGCTACGACTATCA
AATTAAACTTAAACAGCAAGAGGGAGCTCGCCAGATCGCTCGCAAAGAGTGGAAAG
AGATTGGGAAAATTAAAGAAATTAAAGAGGGTTACCTGTCGCTGGTAATTCACGAA
ATCTCGAAAATGGTCATCAAATATAATGCAATTATCGCTATGGAGGATCTGTCCTAC
GGGTTCAAGAAGGGACGTTTTAAAGTAGAGCGCCAGGTGTATCAAAAATTCGAAAC
CATGTTGATCAATAAGCTTAACTATTTGGTCTTCAAAGATATTTCGATTACGGAGAA
CGGAGGTTTGTTGAAAGGATATCAGCTGACGTATATCCCAGACAAGTTGAAAAACG
TGGGGCATCAATGTGGATGTATTTTCTATGTGCCCGCGGCCTACACGAGTAAGATCG
ATCCTACCACTGGTTTCGTCAACATTTTCAAATTTAAAGATCTTACCGTGGATGCGA
AGCGCGAATTTATTAAGAAATTTGATAGCATTCGCTATGATTCCGAAAAGAACCTGT
TCTGTTTTACGTTCGACTATAACAATTTCATTACCCAAAACACGGTGATGAGCAAAT
CCTCTTGGTCAGTTTATACATACGGTGTACGTATCAAACGCCGTTTCGTTAACGGAC
GCTTTTCCAATGAGTCTGATACAATCGATATCACGAAAGATATGGAAAAAACATTAG
AGATGACTGATATCAACTGGCGTGACGGGCACGACCTGCGTCAAGACATTATTGACT
ACGAGATTGTGCAGCATATCTTCGAAATCTTTCGCTTAACTGTGCAAATGCGTAACT
CGTTATCCGAGTTAGAAGACCGTGACTACGATCGCCTGATTTCACCCGTCTTGAACG
AAAATAACATCTTCTACGATTCCGCGAAGGCTGGGGACGCATTGCCCAAGGACGCA
GACGCGAATGGAGCGTACTGTATTGCGCTTAAAGGATTATATGAAATCAAGCAGAT
CACCGAAAATTGGAAGGAGGACGGGAAGTTCTCACGCGACAAACTGAAGATTTCAA
ATAAGGACTGGTTCGATTTCATTCAGAATAAGCGTTACCTGAAACGTCCGGCAGCGA
CCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAG
CCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGG
GCTAA
SEQ ID NO: 49
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAATGGTACGAACAACTTTCAGAACTTCATCGGCATCTCCAGCCTTCAAAAGACTTT
ACGCAACGCATTGATTCCCACGGAGACTACGCAACAGTTTATCGTAAAAAATGGTAT
TATCAAAGAAGATGAATTACGCGGGGAGAATCGCCAGATTCTTAAGGACATTATGG
ACGATTATTACCGTGGATTCATCAGTGAGACACTGAGCTCCATTGATGACATCGACT
GGACGTCATTGTTTGAAAAGATGGAAATCCAGTTGAAAAATGGCGATAACAAAGAT
ACATTGATTAAAGAGCAGACAGAGTACCGCAAAGCAATTCACAAGAAATTCGCCAA
TGATGATCGTTTTAAGAACATGTTTAGTGCCAAGCTTATTTCGGATATCTTACCCGAA
TTCGTGATTCACAACAACAATTATTCGGCAAGTGAGAAAGAGGAAAAGACCCAGGT
TATCAAATTGTTTTCGCGCTTCGCCACTTCGTTCAAAGATTATTTCAAGAACCGTGCA
AACTGTTTCTCCGCTGACGACATCAGTTCCAGCTCATGCCACCGTATTGTAAATGAC
AATGCGGAGATCTTTTTCAGTAATGCCTTAGTATATCGTCGCATTGTAAAGAGCTTA
TCTAATGATGACATTAACAAGATCTCGGGTGATATGAAGGACTCACTTAAGGAGAT
GAGTCTGGAAGAGATCTACTCCTACGAAAAATACGGGGAATTCATCACCCAGGAGG
GAATTTCATTCTACAACGATATCTGCGGCAAAGTTAACTCCTTTATGAATCTGTACTG
TCAAAAGAACAAGGAGAATAAAAACCTGTATAAATTGCAGAAACTTCATAAACAAA
TTTTGTGTATCGCAGACACGAGTTATGAAGTACCTTATAAATTCGAATCCGACGAAG
AGGTATATCAGTCCGTAAATGGGTTCCTGGACAATATCAGTAGTAAGCACATTGTGG
AACGCTTACGCAAAATTGGAGACAATTACAACGGGTATAACCTGGACAAAATCTAC
ATCGTATCCAAATTTTATGAAAGCGTGTCTCAAAAAACTTATCGTGATTGGGAAACA
ATCAACACGGCTCTTGAGATCCATTACAATAACATCTTGCCGGGTAACGGCAAATCG
AAGGCAGACAAAGTTAAAAAAGCAGTTAAGAACGACTTACAGAAAAGCATTACGG
AGATTAACGAGTTAGTAAGTAATTACAAATTATGCTCCGACGATAATATCAAAGCTG
AAACCTACATCCATGAAATTAGCCACATTTTGAACAATTTCGAAGCGCAGGAGCTGA
AATATAACCCTGAAATCCATCTGGTAGAGTCTGAGTTGAAGGCGTCAGAACTGAAA
AACGTTCTTGACGTCATCATGAATGCCTTTCACTGGTGTAGTGTTTTTATGACTGAGG
AGCTTGTAGATAAGGACAACAACTTCTATGCTGAACTTGAAGAGATCTACGATGAA
ATCTACCCCGTAATCAGTCTGTATAATTTAGTTCGTAACTACGTCACGCAGAAACCC
TATTCGACTAAGAAAATTAAGCTGAACTTTGGGATCCCTACTTTGGCAGACGGGTGG
AGCAAGAGTAAAGAATACAGTAATAATGCAATTATCTTGATGCGCGATAACTTATAT
TACTTAGGTATTTTCAATGCTAAGAACAAACCTGATAAGAAGATTATCGAAGGAAAT
ACGAGTGAGAATAAGGGAGACTACAAAAAGATGATTTACAACTTGCTGCCAGGGCC
TAATAAGATGATTCCAAAAGTTTTTCTGTCGAGCAAGACAGGGGTTGAAACTTATAA
GCCATCCGCTTATATCCTTGAGGGGTACAAGCAGAATAAGCATATCAAGTCCTCCAA
AGATTTTGATATTACATTTTGCCACGACTTAATTGATTACTTCAAGAACTGCATCGCA
ATCCATCCCGAATGGAAGAATTTCGGCTTCGATTTCTCAGATACGTCCACGTATGAG
GATATCTCAGGCTTTTACCGCGAAGTTGAGCTGCAAGGTTATAAAATTGATTGGACA
TACATCTCCGAAAAAGACATTGATCTTTTACAGGAAAAGGGCCAATTATACTTATTT
CAAATCTATAACAAAGATTTTAGCAAGAAGTCCACAGGTAATGATAACCTGCATAC
GATGTATTTGAAAAATCTTTTCAGTGAAGAGAATTTGAAGGATATCGTCCTGAAGCT
GAACGGTGAGGCTGAGATCTTCTTCCGCAAATCGTCTATCAAAAACCCCATCATTCA
CAAAAAGGGAAGTATCTTAGTAAACCGCACTTATGAAGCGGAGGAAAAGGATCAGT
TCGGGAACATCCAGATCGTGCGCAAGAACATTCCAGAAAACATCTATCAGGAACTT
TACAAATATTTCAATGACAAGTCTGATAAAGAATTATCAGACGAGGCGGCGAAACT
TAAAAATGTTGTTGGACACCACGAAGCAGCGACGAATATTGTAAAGGATTATCGCT
ACACATACGATAAATACTTTTTGCACATGCCAATCACCATTAACTTTAAGGCGAACA
AGACAGGTTTCATTAACGACCGTATTCTGCAATATATCGCAAAGGAAAAAGACCTG
CACGTTATTGGGATCGATCGTGGCGAACGCAATTTGATCTACGTAAGCGTTATCGAC
ACTTGCGGAAATATCGTTGAACAAAAAAGCTTTAATATCGTCAATGGATACGATTAC
CAAATCAAGCTGAAACAACAAGAAGGGGCACGTCAGATCGCTCGTAAAGAATGGA
AAGAGATTGGTAAGATCAAAGAGATTAAAGAAGGGTATCTTTCTTTAGTAATTCACG
AGATTTCGAAAATGGTTATTAAATACAATGCGATTATTGCTATGGAAGACTTAAGCT
ACGGCTTTAAGAAAGGTCGCTTCAAAGTGGAGCGCCAAGTGTATCAGAAGTTTGAA
ACGATGTTGATTAACAAATTAAATTACCTGGTCTTTAAGGACATCAGTATCACAGAA
AATGGGGGGTTGCTTAAAGGGTACCAGCTTACATACATCCCTGATAAACTGAAAAA
TGTCGGTCATCAGTGCGGATGTATCTTCTATGTACCAGCAGCCTATACCAGTAAGAT
TGACCCTACTACTGGCTTTGTGAATATTTTTAAATTCAAGGATTTAACCGTGGACGCC
AAGCGTGAATTTATTAAAAAATTTGATTCGATTCGCTACGACAGTGAGAAAAACCTT
TTCTGCTTTACCTTTGACTACAACAATTTTATTACCCAGAACACCGTAATGTCAAAGA
GTTCGTGGTCTGTATATACCTACGGTGTTCGCATCAAGCGCCGCTTCGTAAACGGGC
GTTTCAGTAACGAATCTGACACCATCGACATCACTAAAGATATGGAGAAGACATTG
GAAATGACGGACATTAATTGGCGTGATGGCCATGACTTACGTCAGGACATTATTGAT
TACGAAATTGTGCAGCATATCTTCGAGATTTTCCGTTTGACAGTTCAGATGCGCAAC
TCACTGAGTGAGTTAGAAGATCGCGATTACGACCGTCTGATCTCACCGGTCCTTAAT
GAAAACAACATTTTCTACGACTCAGCAAAGGCGGGTGATGCCCTGCCAAAGGATGC
GGACGCTAATGGCGCCTACTGCATCGCCCTGAAAGGATTGTATGAAATTAAGCAGA
TTACAGAAAATTGGAAGGAAGATGGTAAATTTAGCCGTGATAAATTAAAAATCTCG
AACAAGGATTGGTTCGATTTTATTCAGAACAAACGTTATTTGAAACGTCCGGCAGCG
ACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCA
GCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCG
GGCTAA
SEQ ID NO: 50
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAATGGAACAAATAATTTTCAAAATTTTATCGGCATCTCAAGTCTTCAAAAAACCCT
TCGCAATGCCCTGATTCCAACTGAAACAACCCAGCAATTTATCGTCAAGAACGGCAT
CATTAAGGAAGACGAGTTACGCGGGGAGAACCGTCAAATCCTGAAAGATATCATGG
ATGACTACTATCGTGGGTTCATTTCGGAAACCTTGTCTTCAATCGACGACATTGACT
GGACGAGTCTTTTCGAGAAAATGGAAATTCAGCTTAAAAATGGAGACAACAAGGAT
ACTCTGATTAAGGAACAGACAGAATATCGCAAAGCTATCCACAAAAAGTTCGCTAA
TGATGATCGTTTCAAAAATATGTTTTCTGCTAAATTGATTTCCGATATCTTGCCTGAA
TTTGTAATCCACAACAACAATTATTCTGCTTCCGAGAAGGAAGAGAAGACCCAGGTC
ATTAAATTATTCAGCCGCTTTGCAACCAGCTTTAAAGACTACTTTAAGAATCGCGCT
AACTGCTTTTCGGCGGATGACATCTCATCATCATCATGCCACCGCATTGTGAACGAC
AATGCGGAGATCTTCTTTTCGAATGCGTTAGTTTATCGTCGCATTGTCAAAAGTCTTA
GCAATGATGACATCAACAAGATCTCAGGAGACATGAAAGATTCCTTAAAGGAGATG
TCTCTTGAGGAAATCTATTCGTATGAGAAATACGGCGAGTTCATTACCCAGGAAGGT
ATTAGTTTCTACAATGATATCTGCGGCAAAGTAAATTCTTTTATGAATCTGTATTGCC
AAAAAAACAAAGAAAACAAGAATCTTTATAAGTTACAAAAGTTACATAAGCAAATT
CTGTGCATCGCTGATACATCTTATGAGGTACCCTACAAATTTGAAAGTGATGAGGAG
GTCTATCAGAGTGTCAACGGCTTCTTAGACAACATCTCTTCCAAACATATCGTGGAA
CGCCTGCGTAAAATCGGAGATAACTACAACGGATATAACTTAGATAAAATCTACAT
CGTGTCCAAGTTTTATGAAAGTGTGAGCCAAAAAACATATCGTGACTGGGAAACCA
TTAACACCGCATTGGAAATTCACTATAACAACATTTTGCCAGGCAACGGGAAAAGT
AAGGCGGACAAAGTTAAGAAAGCAGTTAAAAATGACCTGCAAAAAAGCATCACTG
AAATTAACGAATTGGTATCGAATTACAAATTATGTAGCGACGATAATATCAAAGCA
GAAACTTACATTCACGAGATTAGTCACATTTTAAATAACTTCGAGGCCCAGGAATTG
AAATACAATCCCGAAATTCATTTGGTTGAATCAGAACTGAAAGCATCAGAGTTGAA
AAATGTGTTAGATGTCATTATGAATGCGTTTCATTGGTGCTCTGTGTTCATGACCGAG
GAACTGGTTGATAAAGATAACAACTTTTACGCTGAATTGGAGGAGATTTACGATGA
GATTTACCCGGTCATTTCGCTTTATAACTTAGTGCGCAATTATGTGACGCAGAAACC
ATATTCCACGAAGAAAATCAAACTTAATTTTGGCATCCCTACTCTGGCTGATGGTTG
GTCGAAATCGAAAGAGTACAGCAACAACGCGATCATTCTTATGCGTGACAATCTTTA
CTATTTGGGCATTTTTAATGCCAAGAATAAGCCAGATAAGAAAATCATTGAGGGGA
ATACTTCCGAGAATAAGGGGGATTACAAAAAGATGATCTATAACTTGCTGCCCGGC
CCCAACAAAATGATTCCTAAGGTTTTCTTGTCAAGCAAGACGGGCGTCGAAACATAT
AAGCCGTCAGCTTATATTCTGGAAGGCTATAAACAGAATAAGCACATCAAGTCTTCC
AAGGACTTTGACATCACTTTTTGCCACGATTTGATCGACTACTTTAAGAACTGTATTG
CGATTCATCCGGAATGGAAGAACTTCGGTTTCGACTTTTCCGATACCTCAACATACG
AGGATATCAGCGGCTTCTACCGTGAAGTCGAGCTTCAAGGCTACAAGATCGATTGG
ACATATATTTCAGAGAAGGACATTGATTTGTTACAAGAGAAAGGTCAACTTTACTTA
TTTCAGATCTATAACAAAGACTTTTCGAAGAAATCGACAGGAAACGATAACTTACAC
ACTATGTATTTAAAAAATCTGTTTTCGGAGGAAAACCTGAAAGATATTGTGCTGAAA
CTTAACGGCGAGGCAGAGATCTTTTTCCGTAAAAGCTCAATCAAGAATCCTATCATC
CATAAAAAAGGTAGTATTCTTGTCAACCGCACATATGAAGCGGAGGAGAAGGACCA
ATTCGGAAACATCCAAATTGTCCGTAAGAATATTCCGGAGAACATTTACCAAGAGTT
GTATAAATACTTTAACGATAAGTCAGATAAGGAACTTAGCGATGAGGCGGCGAAGC
TTAAAAACGTAGTTGGGCATCATGAAGCTGCTACCAACATTGTAAAAGATTACCGTT
ACACCTATGACAAGTATTTCTTGCACATGCCCATTACGATCAATTTCAAAGCAAATA
AGACAGGCTTTATCAATGATCGCATCCTGCAGTACATTGCTAAAGAGAAGGATTTGC
ATGTTATCGGTATTGATCGCGGAGAGCGCAATTTGATCTACGTCTCCGTAATCGACA
CTTGCGGTAACATTGTTGAGCAGAAGTCGTTCAACATCGTTAATGGTTATGATTACC
AAATCAAGCTGAAGCAGCAAGAGGGTGCCCGCCAGATCGCGCGTAAGGAATGGAA
AGAAATCGGGAAAATTAAAGAGATCAAAGAAGGCTATTTGTCTCTGGTAATTCACG
AAATCAGCAAGATGGTGATCAAGTATAACGCGATCATTGCGATGGAGGATCTTTCTT
ATGGCTTCAAGAAAGGGCGCTTTAAAGTCGAACGCCAGGTCTACCAGAAATTTGAG
ACAATGCTTATCAACAAGCTTAACTATCTTGTATTTAAGGATATTTCCATCACTGAG
AACGGAGGACTTTTAAAGGGGTACCAACTGACGTACATTCCTGATAAGCTGAAGAA
CGTTGGTCATCAATGCGGATGCATCTTCTATGTGCCAGCGGCTTACACCTCCAAAAT
CGATCCCACTACAGGCTTTGTCAATATCTTCAAATTCAAGGATTTGACCGTTGACGC
GAAGCGCGAGTTTATCAAGAAGTTTGATAGCATTCGCTACGACAGCGAAAAAAATT
TATTTTGTTTTACTTTCGACTACAATAACTTTATTACTCAGAACACTGTCATGTCAAA
GAGTTCGTGGAGTGTCTACACGTACGGAGTACGTATTAAGCGCCGTTTCGTCAACGG
ACGCTTCTCAAACGAAAGCGACACGATCGACATCACCAAAGACATGGAAAAAACTC
TTGAGATGACGGATATCAATTGGCGCGACGGCCATGACCTGCGTCAGGATATCATTG
ATTACGAGATCGTTCAGCACATCTTCGAAATCTTCCGCCTTACCGTCCAGATGCGCA
ACAGTTTAAGCGAGCTTGAAGACCGCGACTACGATCGTTTGATTAGCCCCGTTCTGA
ACGAGAATAATATTTTCTACGACAGCGCAAAGGCCGGTGATGCTTTGCCAAAGGAC
GCAGACGCGAATGGAGCCTACTGCATCGCCCTGAAGGGCTTATATGAGATTAAGCA
AATTACCGAAAATTGGAAGGAAGATGGTAAGTTCTCCCGTGATAAGCTTAAAATTA
GCAATAAGGATTGGTTCGACTTCATCCAGAACAAACGTTACCTGAAACGTCCGGCA
GCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAG
GCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTAT
TCCGGGCTAA
SEQ ID NO: 51
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAACGGAACAAACAATTTCCAAAACTTCATCGGTATCTCTTCGTTGCAGAAGACTCT
GCGTAATGCTTTGATCCCGACGGAGACAACCCAACAATTTATCGTCAAAAACGGTAT
TATTAAGGAGGACGAGTTACGTGGAGAAAATCGTCAAATCCTTAAGGACATCATGG
ACGATTATTATCGCGGGTTTATTTCTGAAACCCTGAGCAGTATCGATGATATCGACT
GGACCTCACTTTTTGAGAAAATGGAGATCCAGTTGAAGAACGGTGATAACAAAGAC
ACTCTGATCAAAGAGCAAACTGAATACCGCAAGGCAATTCACAAAAAGTTCGCCAA
CGACGACCGTTTCAAGAATATGTTCTCAGCTAAGTTAATCAGCGACATTTTGCCAGA
GTTCGTTATCCACAACAATAATTATAGTGCTTCAGAGAAGGAGGAAAAAACCCAAG
TGATTAAACTTTTTTCGCGCTTTGCAACCTCATTCAAGGACTACTTCAAGAATCGCGC
GAATTGCTTCAGTGCGGACGACATTTCTTCTTCAAGTTGCCATCGTATCGTTAACGAT
AACGCGGAAATTTTCTTCTCTAATGCTTTGGTGTATCGCCGCATTGTAAAATCGCTTA
GTAACGATGACATTAATAAGATCTCAGGTGATATGAAAGATTCATTGAAGGAAATG
AGCTTGGAAGAGATTTACAGTTACGAAAAATATGGAGAATTTATTACTCAGGAAGG
CATCTCATTCTATAACGATATCTGCGGGAAGGTAAATTCGTTTATGAACTTATATTGC
CAGAAAAATAAAGAGAATAAAAATTTGTATAAGCTTCAGAAGTTGCACAAACAGAT
CCTGTGCATTGCAGACACCTCGTATGAGGTTCCGTATAAATTTGAGTCCGATGAAGA
AGTGTATCAGTCTGTGAATGGTTTCTTAGATAATATCTCTTCCAAGCATATTGTCGAA
CGCCTGCGCAAAATTGGTGATAACTATAACGGATACAATCTGGATAAAATTTACATC
GTTTCTAAATTTTACGAGTCAGTCTCGCAGAAGACCTACCGCGACTGGGAAACAATT
AACACGGCATTGGAGATTCACTACAATAATATCTTGCCTGGTAACGGTAAGTCTAAG
GCAGATAAGGTAAAAAAAGCTGTGAAAAACGACCTTCAGAAAAGCATCACGGAGA
TTAATGAGCTGGTGAGTAATTACAAATTATGTTCAGACGATAATATTAAAGCTGAAA
CGTATATCCATGAAATCTCGCATATCTTGAACAACTTCGAGGCCCAAGAACTTAAAT
ATAACCCCGAAATCCATTTAGTCGAGTCTGAATTGAAAGCGTCGGAATTAAAAAAC
GTCTTAGACGTCATTATGAACGCGTTTCACTGGTGTTCAGTTTTCATGACCGAAGAG
CTGGTCGACAAAGACAACAACTTCTATGCGGAATTGGAGGAAATCTATGATGAAAT
CTACCCTGTTATTTCACTGTATAACCTTGTGCGCAACTATGTCACTCAGAAGCCGTAT
TCGACCAAAAAAATTAAATTGAATTTCGGTATCCCTACTCTTGCAGACGGATGGAGT
AAAAGCAAGGAATACAGTAATAACGCCATTATTCTTATGCGCGACAATTTATACTAC
CTGGGCATCTTTAACGCAAAGAATAAGCCGGATAAGAAGATTATTGAGGGTAACAC
CAGTGAGAACAAGGGCGACTATAAGAAGATGATCTATAACTTATTGCCAGGTCCAA
ATAAAATGATCCCAAAAGTATTCTTATCATCAAAGACGGGAGTTGAAACCTATAAG
CCTAGTGCCTATATTCTTGAGGGATATAAACAGAACAAGCACATTAAGTCGTCTAAG
GATTTTGACATTACGTTCTGCCATGACTTAATCGACTATTTTAAAAACTGTATTGCGA
TTCACCCCGAATGGAAGAATTTTGGATTCGATTTTTCGGATACCTCGACCTATGAAG
ATATTTCGGGATTTTATCGTGAAGTGGAGTTGCAAGGCTATAAAATCGATTGGACCT
ATATCTCAGAAAAAGACATTGATTTATTACAGGAAAAGGGACAACTGTACCTTTTCC
AAATTTATAACAAGGACTTTTCTAAAAAGTCCACAGGAAATGATAACCTTCACACCA
TGTACCTGAAGAACCTTTTCTCAGAGGAAAACCTGAAGGACATTGTCCTTAAGTTAA
ATGGAGAAGCGGAGATCTTTTTCCGTAAATCTAGTATCAAGAATCCGATTATCCATA
AAAAAGGTTCGATTTTGGTAAATCGCACCTATGAAGCGGAAGAGAAAGATCAATTT
GGTAACATCCAGATCGTGCGCAAGAATATCCCGGAGAACATTTACCAAGAGCTGTA
TAAGTACTTCAATGATAAGTCTGATAAGGAACTGTCAGATGAAGCTGCGAAATTGA
AGAACGTGGTTGGGCATCATGAAGCCGCTACCAATATCGTCAAGGATTACCGTTATA
CCTATGACAAATATTTCTTACACATGCCGATTACGATCAATTTTAAGGCAAACAAGA
CAGGATTCATCAACGACCGTATCTTGCAGTATATTGCCAAAGAGAAGGATCTGCATG
TGATCGGTATTGACCGCGGGGAGCGCAATTTAATCTATGTATCGGTGATCGATACTT
GTGGTAACATCGTAGAACAAAAGAGCTTTAACATCGTGAATGGTTACGACTATCAG
ATCAAGCTGAAACAACAGGAAGGAGCCCGCCAGATCGCTCGCAAGGAATGGAAAG
AAATCGGGAAAATTAAGGAAATCAAGGAAGGCTACCTTTCATTGGTCATTCACGAA
ATTTCGAAAATGGTAATTAAGTACAACGCGATCATCGCCATGGAGGACCTTTCGTAC
GGATTTAAGAAGGGTCGTTTCAAAGTTGAGCGCCAGGTATACCAAAAATTCGAGAC
TATGCTTATCAACAAACTTAACTACTTGGTCTTTAAGGACATTTCTATTACCGAAAAC
GGCGGCTTACTTAAAGGCTATCAATTGACATATATTCCCGACAAACTGAAGAATGTT
GGACATCAATGCGGGTGTATTTTCTATGTGCCGGCAGCTTACACTAGTAAGATCGAC
CCTACAACCGGGTTCGTAAACATTTTTAAATTCAAAGACTTAACAGTCGATGCGAAG
CGTGAATTTATTAAGAAGTTTGATAGTATCCGCTATGACAGTGAAAAGAACTTGTTT
TGCTTTACGTTCGACTACAATAACTTTATTACACAGAACACGGTCATGTCTAAATCA
TCATGGTCGGTTTACACATATGGGGTGCGCATCAAGCGTCGCTTTGTAAATGGCCGT
TTTAGTAATGAGAGCGACACAATCGACATCACAAAGGATATGGAGAAAACTCTTGA
GATGACAGACATCAATTGGCGTGACGGTCATGACTTACGCCAAGATATCATCGACTA
CGAAATCGTACAGCATATTTTTGAGATTTTTCGTCTTACTGTGCAAATGCGTAATTCT
TTATCCGAACTGGAAGATCGTGATTACGACCGCTTGATTAGTCCCGTCTTAAATGAG
AACAATATTTTCTATGATTCTGCGAAAGCCGGAGATGCACTGCCCAAAGACGCTGAT
GCCAATGGCGCGTATTGCATTGCATTAAAAGGATTATATGAGATTAAACAGATTACC
GAAAATTGGAAAGAGGACGGTAAATTCTCACGCGATAAATTGAAGATTTCTAACAA
GGACTGGTTCGACTTTATCCAAAATAAACGTTATCTTAAACGTCCGGCAGCGACCAA
AAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCG
AAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTA
A
SEQ ID NO: 52
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAACGGTACCAACAACTTTCAGAATTTCATTGGCATTAGCTCGCTTCAAAAAACTTT
ACGCAATGCTCTTATTCCGACTGAGACGACACAACAGTTTATCGTTAAGAATGGCAT
CATCAAAGAAGATGAATTACGCGGAGAAAACCGCCAGATCCTGAAAGACATTATGG
ACGATTATTACCGTGGGTTCATCTCCGAGACGTTGTCATCGATCGATGACATCGACT
GGACGTCACTTTTTGAAAAAATGGAGATCCAGTTAAAGAACGGTGACAATAAGGAT
ACATTGATCAAAGAACAGACCGAGTACCGTAAAGCGATTCATAAAAAGTTTGCGAA
CGATGATCGCTTCAAGAATATGTTTTCTGCGAAATTAATTTCCGACATTTTACCTGAA
TTTGTTATTCATAATAACAACTACTCGGCGTCTGAGAAAGAGGAGAAAACCCAAGT
GATTAAACTTTTTTCACGTTTCGCAACGTCGTTCAAAGACTATTTTAAAAATCGTGCT
AATTGCTTTAGCGCGGATGACATCAGCTCTAGTTCATGTCATCGCATTGTCAACGAT
AATGCTGAGATCTTTTTCAGTAATGCGTTAGTGTACCGTCGTATTGTGAAGTCCTTAT
CTAATGATGATATCAATAAGATCAGCGGGGATATGAAGGACTCACTTAAGGAGATG
AGCTTGGAGGAAATCTATTCCTATGAGAAGTATGGTGAGTTTATTACGCAAGAAGG
AATTAGCTTTTACAACGATATCTGTGGAAAGGTGAATTCGTTTATGAATTTGTATTGC
CAGAAAAATAAGGAGAACAAGAACCTTTATAAATTGCAAAAGTTACACAAGCAAAT
CCTGTGCATTGCAGATACTTCCTACGAGGTGCCTTACAAGTTTGAATCCGACGAAGA
GGTCTACCAATCTGTAAACGGTTTCTTAGATAATATTAGTTCCAAGCATATTGTGGA
GCGCCTTCGTAAAATTGGCGATAATTACAACGGTTACAATTTAGACAAAATTTACAT
TGTCAGTAAATTCTACGAGTCCGTATCTCAAAAGACGTATCGTGATTGGGAGACTAT
CAATACGGCCCTGGAGATCCACTACAACAATATCTTGCCCGGTAATGGTAAGTCGAA
GGCCGATAAAGTTAAGAAAGCGGTGAAAAATGACTTACAGAAGTCAATCACCGAAA
TTAACGAATTGGTGTCCAATTATAAATTGTGTTCAGATGATAATATCAAAGCCGAGA
CCTACATTCATGAGATTTCCCATATCTTAAATAATTTCGAGGCGCAAGAGCTTAAGT
ATAACCCAGAAATCCACCTGGTAGAATCTGAGTTGAAGGCGTCAGAGTTAAAAAAT
GTTTTAGATGTCATTATGAACGCGTTTCACTGGTGCTCCGTATTTATGACGGAGGAA
TTAGTAGATAAAGACAACAATTTCTATGCCGAACTTGAGGAAATCTATGATGAGATC
TATCCCGTCATTAGCCTGTATAACTTGGTCCGCAACTATGTTACCCAAAAACCGTAC
AGTACCAAGAAGATTAAGCTGAATTTCGGCATTCCTACACTGGCTGATGGTTGGAGT
AAATCGAAGGAATATTCGAATAACGCGATTATCTTGATGCGCGACAACTTATACTAT
TTGGGGATCTTTAACGCCAAAAACAAACCGGATAAGAAGATTATTGAGGGAAACAC
ATCAGAGAACAAAGGCGACTACAAAAAAATGATTTACAACTTGTTACCGGGGCCTA
ACAAAATGATCCCGAAGGTGTTCTTATCCAGTAAAACAGGCGTTGAGACCTACAAA
CCTTCCGCATACATCCTGGAAGGGTATAAGCAGAACAAGCACATTAAGTCCAGCAA
GGATTTCGATATTACCTTCTGTCATGATTTAATTGACTATTTCAAGAACTGTATTGCA
ATCCACCCCGAGTGGAAGAACTTCGGATTCGACTTCTCAGATACGAGCACATATGAG
GACATCTCGGGGTTCTATCGTGAAGTAGAACTGCAGGGATATAAAATTGATTGGAC
ATATATTTCCGAAAAAGACATCGACCTTTTACAAGAGAAGGGTCAACTTTACTTGTT
CCAAATTTACAATAAAGACTTCTCAAAAAAAAGCACGGGTAACGATAATTTACACA
CTATGTATTTAAAGAACCTTTTCTCGGAAGAGAATTTAAAGGATATCGTATTGAAGT
TGAATGGAGAAGCGGAGATCTTCTTCCGTAAGTCCAGTATTAAAAACCCTATTATTC
ACAAGAAGGGATCGATTTTAGTTAACCGCACATACGAGGCCGAAGAGAAGGACCAA
TTTGGGAACATTCAAATTGTCCGCAAAAACATCCCTGAGAACATTTATCAAGAGCTT
TATAAGTACTTTAACGATAAGTCCGATAAGGAATTGTCAGATGAGGCGGCAAAGTT
GAAGAATGTCGTGGGGCATCATGAAGCTGCCACCAACATTGTGAAGGACTACCGCT
ACACTTACGACAAATACTTCCTGCACATGCCCATTACGATCAATTTTAAGGCCAATA
AGACAGGCTTTATTAACGACCGTATTCTTCAATATATCGCTAAGGAGAAGGACCTTC
ATGTGATTGGGATCGACCGCGGAGAACGTAATTTAATTTATGTGTCCGTCATCGATA
CGTGTGGAAATATCGTGGAACAGAAATCATTCAATATCGTGAATGGCTATGATTACC
AGATCAAATTAAAACAGCAGGAGGGCGCTCGCCAAATTGCGCGTAAGGAATGGAAA
GAGATCGGAAAAATCAAAGAAATCAAAGAAGGATATTTGTCATTGGTGATCCATGA
GATTTCAAAAATGGTAATTAAATATAATGCAATTATCGCAATGGAAGACCTGTCCTA
TGGTTTTAAGAAGGGTCGTTTCAAGGTAGAACGCCAAGTGTATCAAAAGTTCGAGA
CGATGCTGATCAATAAGCTGAATTATCTTGTGTTTAAGGACATTAGCATCACGGAAA
ATGGAGGGCTGTTGAAAGGCTATCAACTGACGTATATCCCTGACAAGCTGAAAAAT
GTTGGCCATCAGTGCGGGTGCATTTTCTACGTCCCCGCGGCGTATACAAGCAAGATC
GATCCTACTACGGGATTCGTAAATATTTTTAAATTCAAAGACTTAACCGTGGACGCC
AAGCGCGAATTCATTAAGAAGTTTGATAGCATTCGCTACGATTCAGAAAAAAATCTT
TTCTGTTTTACGTTCGATTACAACAATTTTATCACCCAGAACACAGTGATGAGCAAG
TCATCCTGGTCTGTCTATACCTACGGTGTCCGTATCAAACGCCGCTTCGTCAACGGA
CGCTTCTCTAATGAATCTGATACCATTGACATCACCAAGGACATGGAAAAGACACTT
GAGATGACAGATATTAACTGGCGTGACGGACATGACCTGCGTCAGGACATCATCGA
TTATGAGATTGTTCAGCATATCTTCGAGATCTTCCGCCTGACAGTACAAATGCGCAA
TTCACTGTCAGAACTTGAAGACCGCGACTATGACCGCCTGATCTCTCCAGTATTAAA
TGAGAACAATATCTTTTATGACAGTGCTAAGGCCGGCGATGCCCTTCCGAAAGATGC
TGATGCTAACGGAGCTTATTGTATTGCATTAAAGGGTCTTTATGAGATCAAGCAAAT
TACCGAGAATTGGAAGGAGGATGGCAAATTCTCGCGCGACAAACTGAAAATCAGTA
ACAAGGACTGGTTCGATTTTATTCAGAATAAACGTTACCTGAAACGTCCGGCAGCGA
CCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAG
CCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGG
GCTAA
SEQ ID NO: 53
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAACGGAACGAACAACTTCCAGAACTTCATCGGCATCAGTTCTTTACAAAAAACCCT
GCGTAACGCCCTTATTCCGACTGAGACAACACAACAGTTCATCGTTAAAAACGGAAT
TATCAAAGAGGACGAGTTGCGCGGCGAGAATCGCCAAATTTTGAAAGATATTATGG
ACGACTATTATCGTGGTTTTATTTCAGAAACACTGAGTTCGATTGACGATATCGATT
GGACGAGCCTGTTTGAGAAAATGGAAATCCAGTTGAAAAATGGCGATAATAAAGAC
ACTTTAATCAAAGAACAAACCGAGTATCGTAAAGCGATCCATAAAAAGTTCGCTAA
TGACGATCGTTTTAAGAATATGTTCAGTGCGAAACTGATTTCAGACATTTTGCCCGA
GTTCGTGATCCATAATAACAACTATTCCGCCTCGGAAAAGGAAGAAAAAACCCAGG
TGATTAAGCTGTTCAGTCGCTTCGCAACATCTTTCAAGGATTATTTCAAGAATCGCG
CGAATTGCTTCAGTGCGGACGATATTTCTAGTTCAAGCTGCCATCGTATCGTTAATG
ATAACGCGGAGATTTTTTTTAGCAATGCTCTGGTGTACCGCCGCATTGTTAAGTCACT
GTCCAACGATGATATTAACAAGATCTCAGGAGACATGAAAGACTCGCTTAAAGAGA
TGAGTCTGGAAGAGATCTATTCTTATGAGAAGTATGGCGAGTTTATTACCCAAGAAG
GAATCTCATTCTACAATGATATTTGTGGAAAGGTGAACAGCTTTATGAATCTTTACT
GCCAAAAAAACAAGGAGAATAAGAATCTTTACAAACTTCAGAAGTTACATAAACAG
ATTTTGTGTATTGCGGATACGTCTTATGAAGTCCCCTACAAATTTGAATCGGATGAA
GAGGTATACCAAAGTGTGAACGGATTCTTGGACAATATTTCTTCTAAACATATTGTT
GAACGCTTACGTAAGATCGGGGATAACTACAATGGCTACAATCTTGACAAAATCTA
CATTGTTAGCAAATTCTACGAGAGTGTCAGCCAAAAGACGTACCGCGATTGGGAAA
CAATTAATACTGCGCTTGAGATTCACTATAATAACATTTTACCAGGCAACGGCAAGT
CCAAGGCGGATAAAGTTAAAAAAGCTGTTAAAAACGATTTGCAAAAATCTATCACA
GAAATTAACGAGTTAGTTAGTAACTACAAACTGTGCTCCGATGACAACATTAAGGCT
GAGACGTATATCCATGAGATCTCTCACATCTTAAACAATTTTGAAGCTCAAGAACTT
AAGTACAATCCGGAAATCCACCTGGTGGAATCCGAGCTGAAGGCTAGCGAACTGAA
GAACGTATTGGACGTGATCATGAACGCGTTCCACTGGTGTTCTGTCTTTATGACGGA
AGAGCTTGTCGACAAAGATAATAACTTTTACGCGGAACTTGAGGAAATTTACGATG
AGATTTACCCAGTTATTTCATTGTATAACCTTGTCCGTAATTACGTGACCCAAAAGCC
TTATAGTACGAAAAAAATCAAATTAAATTTTGGAATCCCAACACTGGCTGACGGTTG
GAGCAAATCTAAGGAGTATTCTAATAACGCAATCATCTTAATGCGTGACAACCTGTA
TTATTTGGGTATCTTCAATGCCAAAAATAAGCCTGACAAAAAGATTATCGAAGGAA
ATACTTCGGAGAATAAGGGGGATTACAAAAAAATGATTTACAATTTGCTGCCCGGG
CCGAACAAGATGATCCCCAAAGTGTTCTTATCCTCGAAGACTGGTGTAGAAACATAC
AAGCCAAGCGCATACATTCTGGAGGGTTACAAGCAAAACAAACACATCAAATCTTC
AAAAGACTTTGACATTACATTTTGCCATGATCTTATTGACTACTTCAAAAACTGCATT
GCTATTCACCCCGAGTGGAAGAACTTTGGGTTTGACTTCAGCGACACGTCTACGTAT
GAGGACATCTCCGGGTTCTACCGTGAAGTTGAGTTACAAGGGTATAAGATTGACTGG
ACGTATATTTCAGAGAAAGATATCGATCTTTTGCAGGAAAAGGGCCAGTTATATTTA
TTCCAGATTTACAACAAGGACTTTAGTAAGAAGTCAACAGGAAATGACAACTTGCA
TACGATGTATTTGAAAAATCTTTTTTCTGAGGAAAATCTTAAGGACATCGTACTGAA
ATTGAATGGCGAGGCTGAAATCTTCTTCCGTAAATCCTCCATTAAGAATCCCATTAT
CCACAAAAAGGGGTCTATCCTGGTGAATCGTACCTACGAGGCAGAGGAGAAGGATC
AATTCGGAAATATTCAGATTGTTCGTAAGAACATCCCCGAGAACATTTATCAAGAAT
TGTATAAGTACTTTAATGACAAATCTGACAAAGAGTTATCCGACGAAGCTGCGAAA
CTGAAAAACGTTGTTGGTCACCACGAGGCCGCCACTAATATCGTAAAAGACTACCGT
TATACCTATGACAAGTACTTTTTGCACATGCCGATCACTATCAACTTCAAGGCGAAT
AAGACGGGCTTCATTAACGATCGTATCCTGCAATACATCGCCAAGGAGAAGGACCT
TCACGTCATTGGGATTGACCGTGGTGAGCGTAACCTGATTTATGTAAGCGTCATTGA
TACCTGCGGTAATATCGTCGAACAGAAAAGTTTCAACATTGTAAATGGATATGACTA
TCAGATCAAACTTAAGCAGCAGGAGGGTGCACGCCAGATTGCCCGCAAGGAATGGA
AGGAGATTGGGAAGATTAAGGAAATTAAAGAAGGTTACTTATCACTGGTTATTCAC
GAGATCAGTAAAATGGTAATCAAATATAACGCGATCATTGCCATGGAGGATCTGAG
CTATGGCTTTAAAAAGGGCCGTTTCAAAGTCGAGCGCCAGGTATATCAAAAGTTTGA
AACAATGCTGATTAACAAATTAAACTATCTGGTTTTCAAAGATATTTCGATCACTGA
AAATGGCGGGCTGTTGAAGGGATACCAACTTACATACATCCCTGACAAACTGAAAA
ATGTCGGTCACCAATGTGGATGTATCTTTTATGTACCAGCAGCGTATACGAGCAAAA
TCGATCCAACTACGGGTTTTGTGAACATCTTTAAGTTCAAGGATTTGACAGTAGATG
CCAAACGCGAGTTCATTAAAAAATTTGATTCAATTCGCTACGATTCAGAGAAAAATC
TTTTTTGTTTCACGTTCGATTACAATAATTTCATTACGCAGAACACAGTAATGTCAAA
GTCAAGCTGGTCGGTCTACACGTATGGAGTCCGTATTAAACGTCGTTTTGTAAACGG
CCGTTTCTCAAATGAATCAGATACAATTGATATTACGAAGGATATGGAGAAGACATT
AGAGATGACTGACATTAACTGGCGCGACGGACATGATCTTCGTCAGGACATTATTGA
TTATGAGATTGTACAGCATATCTTTGAGATCTTCCGCCTGACCGTTCAGATGCGCAA
TTCGTTGTCCGAGTTAGAAGACCGCGATTACGACCGTTTAATCAGTCCCGTCTTAAA
CGAAAATAACATCTTCTACGATTCAGCCAAGGCAGGCGATGCCTTGCCAAAGGATG
CTGACGCAAATGGCGCATACTGTATTGCGTTGAAAGGCCTTTATGAAATCAAGCAAA
TTACCGAAAACTGGAAAGAAGACGGAAAATTCTCCCGTGATAAGTTGAAAATCTCT
AATAAGGATTGGTTCGATTTCATCCAAAATAAACGCTATTTGAAACGTCCGGCAGCG
ACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCA
GCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCG
GGCTAA
SEQ ID NO: 54
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAACGGAACTAATAATTTCCAAAATTTTATAGGCATCTCTTCTTTACAGAAGACTCTT
CGTAACGCCCTAATCCCGACTGAGACCACACAACAATTCATAGTGAAAAATGGGAT
CATTAAAGAAGACGAGCTGCGTGGGGAGAACAGGCAGATCCTAAAAGACATAATG
GACGATTATTATAGAGGGTTCATCTCAGAGACATTATCTAGCATCGACGACATTGAC
TGGACCTCCCTGTTTGAAAAAATGGAAATCCAGCTGAAGAATGGTGACAATAAAGA
CACATTAATAAAAGAACAAACAGAGTACAGGAAAGCCATCCACAAGAAGTTCGCAA
ACGATGACAGATTCAAAAATATGTTCAGTGCGAAGCTAATATCCGACATCTTACCAG
AGTTTGTAATACACAATAACAATTACAGCGCGAGCGAAAAGGAAGAGAAAACGCA
AGTAATTAAGCTTTTTAGTAGGTTCGCTACCTCTTTCAAAGATTACTTCAAAAATCGT
GCTAACTGCTTCTCAGCCGACGACATATCTTCAAGTTCCTGTCACCGTATCGTGAAT
GATAACGCTGAGATATTCTTCTCAAACGCCCTTGTATACCGTAGGATCGTAAAGTCC
TTATCTAACGATGATATAAACAAGATCAGTGGAGACATGAAAGACAGCCTTAAAGA
GATGTCTCTAGAAGAAATTTACTCCTATGAAAAGTATGGGGAGTTTATAACACAGGA
GGGGATCAGCTTCTACAACGACATCTGCGGAAAGGTGAACAGTTTCATGAATCTTTA
CTGCCAGAAGAATAAAGAGAACAAAAATCTTTATAAGCTTCAAAAGTTGCACAAAC
AAATACTGTGCATTGCCGATACATCATATGAGGTCCCCTATAAGTTCGAATCTGATG
AGGAAGTTTATCAATCTGTTAACGGCTTTCTAGACAATATCAGCTCAAAACACATCG
TAGAAAGACTGAGGAAAATAGGTGATAATTATAATGGATACAACTTGGATAAAATA
TATATAGTCTCTAAATTTTACGAGTCAGTATCCCAGAAAACGTATAGGGATTGGGAG
ACCATCAACACGGCGTTAGAGATTCATTACAATAACATCTTACCGGGAAACGGAAA
AAGTAAGGCGGACAAAGTAAAGAAAGCCGTTAAAAATGACTTACAAAAGAGTATA
ACAGAAATAAACGAACTAGTAAGCAACTACAAGCTTTGTTCCGATGATAATATCAA
GGCCGAGACATATATCCATGAGATCTCCCACATTCTAAACAATTTCGAAGCGCAAGA
ACTTAAATATAATCCCGAAATCCACCTGGTGGAAAGTGAACTAAAGGCTAGTGAGT
TAAAGAACGTTCTTGATGTTATCATGAACGCCTTCCATTGGTGCTCTGTTTTTATGAC
CGAGGAGTTGGTTGATAAAGATAATAATTTCTACGCTGAATTAGAGGAGATATACG
ACGAAATCTACCCAGTGATTTCACTATACAACTTGGTCAGGAACTATGTTACACAAA
AGCCGTACAGCACTAAGAAAATTAAGCTAAATTTCGGTATCCCCACGTTAGCCGACG
GGTGGAGCAAGTCCAAAGAATATTCCAACAATGCGATTATTTTAATGCGTGACAATC
TTTATTACCTTGGCATCTTCAATGCCAAAAACAAACCTGACAAAAAGATTATAGAAG
GTAATACGTCCGAGAACAAAGGCGATTACAAGAAGATGATTTATAACCTACTGCCC
GGACCAAACAAAATGATCCCCAAAGTTTTTCTTAGTTCTAAAACCGGCGTAGAGACG
TATAAACCTTCTGCCTATATCTTAGAGGGATATAAGCAGAACAAACATATCAAATCT
TCCAAGGACTTTGATATTACATTCTGCCACGATTTAATTGACTACTTCAAAAATTGCA
TAGCGATACATCCGGAGTGGAAGAACTTTGGCTTCGACTTCAGTGATACATCCACCT
ATGAGGATATATCAGGCTTCTATCGTGAGGTCGAATTGCAAGGGTACAAAATCGATT
GGACGTATATATCCGAGAAAGACATAGACCTTCTTCAAGAAAAGGGGCAGTTATAT
TTATTCCAAATATACAACAAGGACTTCAGTAAGAAGTCAACAGGTAATGACAACTT
ACACACCATGTACTTGAAAAATTTATTTTCTGAAGAAAACCTAAAGGACATTGTACT
AAAACTGAACGGGGAGGCAGAAATTTTTTTTAGAAAGAGCAGCATAAAAAACCCAA
TAATTCATAAGAAAGGAAGCATTTTAGTTAATAGGACGTACGAGGCAGAGGAAAAG
GACCAGTTTGGCAATATCCAGATCGTAAGGAAAAATATTCCTGAAAACATATATCA
GGAACTATATAAATACTTTAACGACAAATCCGACAAAGAATTATCCGACGAGGCTG
CAAAGCTGAAGAACGTCGTAGGGCACCATGAGGCAGCGACTAATATTGTGAAAGAC
TATAGGTATACATACGACAAATACTTTCTGCACATGCCCATCACGATTAACTTCAAG
GCGAACAAGACGGGATTCATTAACGACCGTATATTACAATATATTGCTAAGGAGAA
AGATCTGCATGTAATAGGTATCGACAGAGGCGAACGTAATTTAATCTACGTGTCCGT
CATCGACACGTGCGGGAACATCGTAGAGCAAAAGAGTTTTAATATAGTAAATGGCT
ATGATTACCAAATTAAGCTAAAGCAGCAAGAAGGAGCAAGACAGATAGCTAGGAA
AGAATGGAAGGAGATAGGAAAAATAAAGGAGATCAAGGAGGGGTATCTTAGCCTA
GTAATTCATGAAATATCTAAGATGGTTATCAAATACAACGCTATCATAGCGATGGAA
GACTTATCTTATGGTTTCAAGAAAGGAAGGTTCAAAGTAGAGCGTCAAGTTTATCAA
AAGTTCGAAACGATGTTGATTAATAAACTAAACTATTTGGTATTTAAAGATATATCT
ATCACCGAGAATGGTGGTCTACTAAAGGGTTACCAGCTTACATACATACCGGACAA
ACTTAAAAACGTCGGACATCAGTGTGGATGCATTTTCTACGTTCCAGCTGCATATAC
CAGCAAGATCGACCCAACGACTGGGTTCGTAAATATTTTTAAATTCAAGGATTTGAC
TGTCGACGCCAAAAGAGAGTTCATAAAAAAGTTCGATTCAATTAGGTACGACAGCG
AAAAGAATTTGTTCTGCTTTACTTTTGACTATAACAATTTCATTACTCAGAACACTGT
AATGTCTAAGTCCTCTTGGTCAGTCTATACTTATGGCGTTCGTATCAAACGTAGATTT
GTTAACGGTAGATTCTCAAATGAAAGTGATACAATAGATATCACGAAAGATATGGA
GAAAACATTAGAAATGACAGACATAAACTGGAGAGACGGACATGACTTGAGACAG
GACATTATTGACTACGAGATCGTGCAGCACATCTTTGAGATCTTTCGTTTGACCGTA
CAAATGCGTAACAGTTTATCTGAGCTTGAGGACAGGGACTACGATAGATTGATATCA
CCTGTATTAAATGAGAATAACATCTTCTATGATTCCGCAAAAGCAGGCGACGCTCTA
CCCAAAGACGCTGATGCGAACGGTGCTTATTGCATAGCTTTAAAGGGTTTGTATGAG
ATCAAACAGATAACAGAAAATTGGAAGGAAGATGGTAAGTTCTCCCGTGACAAGCT
TAAAATATCAAATAAGGACTGGTTCGATTTTATACAGAATAAGCGTTATTAAAACGT
CCGGCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCG
GCGCAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAA
GGTTATTCCGGGCTAA
SEQ ID NO: 55
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAATGGAACTAATAACTTCCAGAATTTCATTGGTATCTCCTCTTTACAAAAAACTCT
AAGAAACGCCCTAATTCCGACTGAAACTACACAGCAATTCATCGTCAAAAACGGGA
TCATTAAGGAGGATGAGTTGAGGGGTGAAAATCGTCAAATTCTTAAAGACATCATG
GACGACTACTACAGGGGGTTCATCAGCGAGACGTTATCTAGTATAGACGATATAGA
CTGGACTTCACTGTTCGAGAAGATGGAAATCCAATTAAAAAATGGGGACAATAAAG
ATACACTTATAAAGGAACAGACAGAGTATAGAAAGGCAATACACAAAAAGTTTGCC
AACGACGATCGTTTCAAGAACATGTTTAGTGCTAAATTGATTTCAGATATTCTGCCG
GAATTTGTTATTCACAACAATAATTATAGCGCCAGTGAGAAAGAAGAAAAAACGCA
GGTTATCAAACTGTTCAGTCGTTTCGCTACATCTTTTAAGGATTACTTTAAAAACCGT
GCAAATTGTTTTTCAGCCGACGATATTAGTAGCAGCTCTTGTCACCGTATTGTTAATG
ATAATGCGGAGATTTTCTTTTCAAACGCATTGGTCTACAGGAGGATAGTCAAGTCCC
TTTCAAATGACGACATTAATAAGATCTCAGGTGACATGAAAGATTCCTTAAAGGAA
ATGTCCCTGGAAGAGATCTATTCCTATGAAAAGTACGGTGAGTTCATTACTCAAGAG
GGTATAAGCTTTTACAATGACATATGTGGTAAGGTTAATAGCTTTATGAACCTGTAT
TGCCAGAAGAACAAAGAAAATAAGAATCTGTATAAGTTGCAAAAGCTACACAAACA
AATTTTGTGCATTGCCGATACATCATACGAGGTGCCATACAAATTCGAGAGCGATGA
GGAGGTTTATCAGAGCGTGAATGGATTCCTGGACAATATTAGTAGTAAGCATATCGT
GGAAAGGCTTAGAAAGATAGGTGACAATTACAATGGCTACAATCTGGATAAAATCT
ACATCGTCTCAAAATTCTATGAAAGTGTATCCCAGAAGACGTACCGTGATTGGGAAA
CTATCAACACCGCTCTGGAGATACATTACAACAATATACTTCCCGGAAACGGCAAGT
CAAAAGCCGACAAAGTCAAAAAAGCGGTCAAGAACGATTTACAAAAGTCTATCACT
GAAATTAATGAATTAGTTAGTAATTACAAACTGTGTAGTGATGATAATATTAAGGCA
GAGACTTACATACACGAAATTTCACACATTTTAAACAACTTCGAGGCACAGGAACTT
AAATATAATCCTGAAATTCACCTGGTTGAAAGTGAATTGAAAGCCAGCGAGCTAAA
GAACGTTTTGGACGTAATCATGAACGCATTCCACTGGTGCTCTGTCTTTATGACAGA
GGAACTAGTGGATAAGGACAATAATTTTTATGCGGAGCTGGAGGAAATATACGATG
AGATATATCCCGTAATATCATTATATAATCTGGTAAGAAACTATGTGACTCAAAAGC
CGTATAGCACCAAGAAAATTAAACTTAATTTCGGCATACCCACTTTAGCGGACGGCT
GGTCAAAATCCAAAGAGTATAGTAATAATGCCATCATCCTGATGCGTGACAACCTGT
ACTATTTAGGTATATTTAACGCCAAAAATAAACCCGACAAAAAGATTATAGAGGGC
AACACCTCAGAGAACAAAGGTGATTATAAGAAGATGATTTACAACCTTTTACCCGGT
CCTAATAAGATGATTCCCAAAGTCTTTCTATCTAGCAAAACTGGTGTTGAAACATAC
AAACCCTCAGCTTATATTTTAGAAGGGTATAAGCAGAATAAGCATATTAAAAGCTCC
AAAGATTTCGATATTACCTTTTGCCATGACTTGATAGACTATTTCAAAAATTGTATTG
CCATTCACCCTGAATGGAAAAACTTCGGATTTGACTTCTCTGACACATCCACCTACG
AAGACATTTCAGGTTTTTACAGGGAAGTCGAGCTACAGGGTTATAAAATTGATTGGA
CATACATCAGCGAGAAAGATATTGACCTACTTCAAGAAAAAGGGCAGCTATACCTG
TTCCAGATATACAATAAAGACTTCAGTAAAAAAAGCACCGGGAACGATAATCTTCA
CACAATGTACTTAAAAAATTTATTTAGTGAAGAGAATCTGAAGGATATAGTGCTGAA
GTTAAACGGGGAGGCAGAGATATTTTTTAGAAAATCTAGTATTAAGAATCCGATCAT
CCACAAGAAGGGTTCTATCCTTGTTAATAGGACTTATGAGGCAGAAGAAAAAGACC
AATTCGGCAACATACAAATTGTCCGTAAAAATATCCCTGAGAACATTTATCAGGAAC
TATACAAGTACTTCAATGATAAAAGCGACAAGGAGCTGAGCGACGAGGCTGCTAAG
TTAAAGAATGTGGTGGGCCACCATGAGGCAGCAACGAATATTGTGAAGGACTATCG
TTATACCTACGATAAATACTTTCTTCATATGCCGATCACCATTAATTTCAAGGCAAAC
AAAACTGGCTTCATTAACGATCGTATCTTACAATATATCGCAAAAGAGAAAGACCTT
CACGTTATCGGGATCGATAGAGGCGAGCGTAACCTAATTTATGTTTCTGTGATAGAC
ACCTGTGGGAACATAGTCGAACAGAAATCATTTAATATTGTTAACGGCTACGATTAT
CAGATAAAGTTGAAGCAACAAGAGGGTGCACGTCAAATAGCAAGGAAAGAATGGA
AAGAAATAGGCAAGATTAAAGAAATAAAAGAAGGTTATTTATCCCTTGTAATACAC
GAAATTAGCAAAATGGTGATTAAATATAATGCGATCATTGCCATGGAGGATCTTTCT
TACGGCTTCAAAAAGGGGAGATTCAAAGTCGAGAGGCAGGTGTATCAGAAGTTTGA
GACCATGCTAATCAATAAACTAAATTATCTAGTATTCAAAGACATAAGCATCACCGA
AAATGGCGGCTTGTTGAAGGGTTATCAATTGACCTACATCCCAGATAAACTAAAAA
ACGTAGGGCATCAATGCGGATGTATATTTTACGTTCCAGCCGCATACACTTCCAAAA
TCGATCCAACTACGGGTTTTGTGAACATCTTCAAATTCAAAGACTTGACTGTCGATG
CTAAGAGGGAGTTTATCAAGAAATTTGACTCCATTAGATACGACAGTGAGAAGAAT
CTGTTCTGTTTTACCTTTGATTATAACAACTTTATAACTCAAAACACAGTCATGAGTA
AGTCATCTTGGTCAGTGTATACGTATGGTGTGAGGATTAAAAGGAGGTTTGTTAACG
GGAGATTTTCCAATGAAAGTGATACAATAGATATAACCAAGGACATGGAAAAGACT
CTTGAAATGACCGACATTAACTGGAGAGATGGCCACGACTTACGTCAAGATATAAT
CGATTACGAGATAGTGCAACATATCTTTGAGATATTTAGGCTTACTGTCCAAATGCG
TAACTCATTAAGTGAGTTGGAGGACAGGGATTACGATAGGCTAATAAGTCCTGTTCT
TAACGAAAACAATATATTCTACGATTCAGCAAAGGCGGGAGACGCCCTGCCCAAGG
ACGCGGATGCTAACGGCGCATACTGTATTGCCCTGAAAGGCTTGTACGAGATAAAA
CAGATCACGGAGAACTGGAAAGAAGATGGAAAATTCAGTCGTGACAAGTTAAAAAT
TAGTAACAAAGACTGGTTCGACTTTATTCAGAACAAGAGATATCTGAAACGTCCGGC
AGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCA
GGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTA
TTCCGGGCTAA
SEQ ID NO: 56
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAACGGAACCAATAACTTTCAAAACTTTATAGGCATCTCCAGTCTACAGAAGACACT
ACGTAACGCTTTGATACCAACTGAGACCACGCAGCAGTTTATCGTCAAGAACGGTAT
TATAAAGGAAGACGAGCTAAGGGGGGAAAACCGTCAGATCTTAAAGGACATCATGG
ATGACTACTACAGAGGCTTCATAAGTGAGACTTTGTCTAGTATAGACGACATCGACT
GGACCAGTTTATTTGAGAAGATGGAAATTCAGTTAAAGAACGGGGACAATAAAGAC
ACACTAATTAAAGAGCAGACCGAATACAGAAAAGCTATACACAAAAAGTTTGCCAA
CGATGATAGATTCAAAAATATGTTTTCAGCAAAATTGATTTCCGACATATTGCCAGA
ATTCGTAATCCATAATAACAATTATTCTGCAAGTGAGAAGGAAGAGAAGACCCAAG
TAATCAAGCTGTTTTCCCGTTTTGCTACGAGTTTCAAAGATTATTTCAAGAATAGGGC
TAATTGTTTCTCCGCGGACGACATAAGTAGCAGTTCCTGTCACAGGATTGTGAACGA
TAATGCTGAGATATTTTTTTCCAATGCCCTAGTGTATAGGAGAATAGTTAAAAGCTT
AAGCAACGACGATATCAATAAAATTTCAGGGGACATGAAGGACAGCTTAAAGGAAA
TGAGTTTGGAGGAGATTTACAGTTATGAAAAATACGGAGAGTTTATAACTCAGGAA
GGCATCTCTTTCTATAATGATATCTGTGGGAAGGTAAACTCCTTCATGAATTTATATT
GCCAGAAGAATAAGGAAAACAAAAATCTTTACAAGCTTCAAAAGTTACATAAGCAG
ATCTTATGTATTGCCGACACGAGTTATGAAGTGCCTTATAAATTCGAGAGTGATGAG
GAAGTGTATCAGTCTGTTAACGGATTCCTAGATAATATAAGTTCCAAACATATAGTC
GAGAGGCTGAGGAAGATTGGCGATAACTATAATGGATATAATCTTGACAAAATCTA
TATAGTCTCTAAATTTTATGAAAGCGTCAGCCAGAAGACATATAGAGATTGGGAAA
CTATAAACACAGCCCTTGAAATACATTACAATAACATCCTACCCGGCAATGGTAAGT
CTAAGGCAGACAAAGTTAAAAAAGCAGTAAAGAATGACTTACAGAAGTCAATCACG
GAGATAAATGAGTTGGTCAGTAACTACAAATTATGCTCCGACGATAATATTAAGGCC
GAAACATATATACACGAGATAAGTCATATATTAAACAATTTCGAAGCCCAGGAGTT
AAAATATAACCCTGAAATTCATCTGGTCGAAAGTGAGTTAAAGGCCAGTGAGTTAA
AGAATGTACTTGACGTAATTATGAATGCTTTTCATTGGTGCTCCGTGTTCATGACCGA
GGAGTTAGTAGATAAAGACAATAACTTTTACGCCGAACTTGAAGAGATATACGACG
AGATTTATCCGGTAATCAGCTTGTACAACTTAGTTAGAAATTATGTAACACAGAAGC
CTTACTCTACTAAAAAAATAAAACTGAACTTTGGTATCCCAACTCTTGCAGATGGTT
GGAGTAAAAGCAAGGAATATAGCAACAATGCGATCATCTTGATGAGAGACAACTTG
TACTATTTGGGAATCTTCAACGCGAAAAATAAACCCGACAAAAAAATCATCGAAGG
GAATACCTCTGAGAATAAAGGTGACTATAAGAAAATGATTTACAATCTACTTCCTGG
TCCTAATAAAATGATCCCGAAAGTGTTTCTTAGTTCTAAGACTGGTGTCGAGACGTA
CAAACCTAGCGCGTACATCTTAGAAGGGTACAAGCAGAATAAACACATCAAATCAA
GCAAAGACTTCGATATTACTTTTTGCCATGACTTGATAGACTACTTTAAAAACTGCA
TAGCAATCCACCCGGAGTGGAAAAACTTTGGCTTTGATTTCTCTGACACCTCTACAT
ATGAGGACATATCTGGTTTTTACCGTGAGGTTGAATTGCAGGGATACAAAATTGACT
GGACTTACATATCTGAAAAAGATATCGATCTATTGCAGGAGAAAGGCCAGCTTTACC
TTTTCCAGATCTATAATAAGGACTTCTCTAAGAAGTCTACAGGGAATGATAATTTGC
ACACTATGTACTTAAAAAATCTGTTTTCCGAGGAAAACTTGAAAGACATTGTTTTAA
AGTTGAACGGAGAAGCTGAAATATTTTTCAGAAAGAGCTCCATAAAAAACCCGATC
ATTCATAAGAAGGGATCTATCCTGGTTAACAGAACGTACGAAGCGGAAGAAAAAGA
CCAATTCGGAAACATTCAAATTGTTAGAAAGAATATCCCTGAGAACATCTACCAGG
AGTTATATAAGTATTTTAATGATAAGTCAGATAAGGAACTATCTGACGAAGCGGCG
AAGCTTAAAAATGTTGTAGGACACCATGAGGCTGCTACAAATATAGTCAAGGACTA
CCGTTATACCTACGATAAGTACTTTCTACACATGCCCATTACCATCAATTTTAAAGCT
AATAAAACGGGTTTTATCAACGATCGTATCCTACAATATATTGCGAAAGAGAAGGA
TTTGCATGTCATTGGCATTGATAGAGGTGAGAGGAACCTAATATACGTATCCGTGAT
TGATACGTGCGGGAACATAGTTGAACAGAAATCATTTAATATAGTTAATGGGTACG
ACTATCAGATTAAGCTAAAGCAACAAGAAGGCGCCAGGCAAATTGCCCGTAAAGAA
TGGAAAGAGATCGGGAAGATCAAGGAAATAAAAGAAGGATACCTTTCCCTGGTCAT
CCATGAAATTAGCAAAATGGTGATTAAGTACAATGCCATAATCGCGATGGAGGACT
TAAGCTACGGGTTCAAAAAGGGGAGGTTTAAGGTGGAGAGGCAAGTGTACCAGAAA
TTTGAGACCATGCTAATCAACAAACTGAACTACCTAGTTTTTAAGGACATTTCAATT
ACAGAGAATGGAGGACTTTTAAAGGGTTACCAACTAACGTATATACCAGATAAGTT
GAAAAATGTCGGTCACCAGTGTGGCTGCATCTTTTACGTTCCCGCCGCTTATACATCT
AAAATTGATCCAACCACAGGCTTTGTAAATATCTTTAAATTCAAAGATTTAACTGTG
GATGCAAAAAGAGAGTTTATCAAGAAATTCGATAGCATTCGTTATGATAGCGAGAA
GAACCTGTTCTGCTTTACTTTCGACTATAACAACTTTATAACTCAAAACACCGTGATG
TCAAAAAGCTCATGGTCAGTCTACACCTATGGTGTAAGGATTAAAAGGCGTTTCGTG
AATGGGAGATTCTCCAATGAAAGTGACACGATCGACATAACAAAGGACATGGAGAA
GACACTAGAGATGACTGATATTAATTGGAGAGACGGACACGATCTGCGTCAAGATA
TAATTGATTATGAGATAGTACAGCACATATTTGAGATCTTCCGTTTGACTGTCCAAA
TGCGTAATTCCCTTTCTGAGCTGGAAGATAGGGACTATGATAGATTAATATCCCCTG
TACTAAATGAGAACAACATTTTCTATGATAGTGCAAAAGCCGGGGATGCATTGCCG
AAAGACGCTGACGCTAATGGGGCGTACTGTATAGCTTTAAAGGGGCTTTACGAAAT
AAAGCAGATAACCGAAAACTGGAAGGAAGATGGCAAATTCTCAAGGGACAAACTT
AAGATCTCTAACAAGGATTGGTTCGATTTTATACAAAACAAACGTTATTTGAAACGT
CCGGCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCG
GCGCAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAA
GGTTATTCCGGGCTAA
SEQ ID NO: 57
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAATGGTACAAACAACTTTCAGAATTTCATTGGGATCTCTAGCTTACAGAAGACCCT
GAGGAATGCGTTGATTCCAACTGAAACAACCCAGCAATTCATCGTGAAAAATGGGA
TAATCAAAGAGGATGAGTTAAGGGGTGAAAACCGTCAAATATTGAAGGATATTATG
GACGACTACTACCGTGGATTCATCTCAGAGACGTTGAGCAGCATTGACGACATAGA
CTGGACTAGCCTTTTCGAGAAGATGGAAATTCAGTTAAAGAACGGAGATAACAAAG
ATACACTAATCAAGGAACAGACAGAATACAGAAAAGCAATTCATAAGAAATTCGCT
AATGACGATCGTTTTAAAAACATGTTCTCTGCAAAATTAATTAGCGACATTCTGCCG
GAATTCGTTATACATAATAATAACTACAGTGCTTCTGAAAAGGAAGAGAAAACTCA
GGTAATAAAACTGTTCTCTCGTTTTGCCACATCCTTCAAAGACTACTTTAAAAATAG
AGCGAACTGCTTTAGCGCCGACGATATTAGTTCTTCCTCATGCCACAGGATTGTCAA
CGATAATGCAGAGATATTCTTTTCTAACGCACTAGTCTACAGAAGGATTGTAAAGTC
TTTGTCAAATGATGACATAAACAAGATTAGTGGAGATATGAAAGACTCTCTAAAGG
AAATGAGCCTTGAGGAGATATACTCTTATGAAAAGTACGGTGAGTTTATTACCCAAG
AAGGCATTAGTTTCTATAATGACATTTGTGGAAAAGTTAACAGTTTTATGAATCTAT
ACTGTCAAAAAAATAAGGAGAATAAAAATCTTTATAAGTTGCAAAAACTGCATAAG
CAGATATTATGTATAGCAGACACGAGCTATGAGGTACCGTACAAGTTCGAGAGCGA
TGAGGAAGTCTACCAATCTGTCAACGGATTTTTGGACAACATTTCTTCAAAACATAT
TGTGGAGAGGCTTAGGAAAATAGGCGACAATTATAATGGATATAACTTAGATAAGA
TATATATTGTTTCCAAATTCTACGAATCTGTAAGCCAGAAGACATACAGAGATTGGG
AAACGATAAACACAGCCCTTGAAATTCACTATAACAACATACTACCTGGAAACGGC
AAATCAAAGGCCGACAAAGTTAAGAAGGCCGTAAAGAATGATTTACAGAAGAGCAT
AACGGAGATCAATGAGCTGGTGTCTAACTATAAATTGTGTAGCGATGACAACATAA
AAGCCGAGACTTACATTCACGAAATTTCACACATACTTAACAACTTTGAAGCTCAGG
AATTAAAGTATAATCCCGAAATACACCTTGTGGAGTCCGAACTAAAGGCTAGTGAG
CTTAAGAACGTCCTAGACGTAATTATGAATGCCTTCCACTGGTGTAGTGTTTTTATGA
CCGAGGAACTTGTTGACAAAGATAATAATTTTTATGCAGAACTAGAAGAGATATAC
GATGAAATATACCCGGTGATCAGTTTGTACAATCTTGTCAGGAACTATGTGACACAA
AAGCCCTATTCAACAAAGAAAATAAAACTTAATTTCGGAATTCCTACGTTAGCTGAT
GGCTGGTCTAAATCCAAGGAATACAGCAACAACGCTATAATTCTGATGAGAGATAA
CTTGTACTATCTAGGCATCTTCAATGCCAAAAATAAGCCTGATAAGAAGATTATAGA
GGGCAACACTTCAGAGAACAAGGGCGACTACAAGAAAATGATCTATAACCTATTGC
CTGGCCCAAACAAGATGATTCCGAAGGTCTTCCTATCATCCAAGACCGGCGTTGAGA
CATACAAGCCATCAGCGTATATTTTAGAGGGGTACAAACAAAACAAGCACATAAAG
TCTAGTAAAGACTTCGATATAACATTTTGTCATGACTTAATTGACTACTTTAAGAATT
GCATCGCTATACACCCGGAATGGAAGAATTTCGGCTTCGACTTCTCTGATACATCTA
CCTACGAGGACATTAGCGGGTTTTACCGTGAAGTCGAATTACAAGGGTATAAGATA
GATTGGACGTACATCTCTGAGAAAGACATAGACTTGCTTCAGGAAAAGGGCCAGTT
GTATCTATTCCAAATATACAATAAGGATTTTTCCAAGAAATCTACGGGTAATGACAA
TCTTCACACAATGTATCTTAAGAACCTTTTCTCAGAAGAGAACCTGAAGGACATTGT
CTTAAAACTAAATGGCGAAGCTGAGATTTTTTTCAGGAAGTCTTCAATTAAGAACCC
GATAATCCACAAGAAGGGGAGTATTCTTGTGAATAGAACTTACGAGGCCGAAGAAA
AAGACCAATTTGGTAACATCCAGATAGTCAGAAAGAACATTCCAGAGAACATCTAC
CAAGAGCTATACAAATATTTCAACGACAAGTCCGATAAGGAACTGTCCGATGAGGC
AGCCAAGTTGAAGAATGTCGTGGGTCATCATGAAGCTGCTACTAACATTGTCAAGG
ACTATCGTTATACTTACGACAAGTATTTCCTACACATGCCGATAACAATTAATTTCA
AGGCTAACAAAACAGGCTTTATCAACGATCGTATCTTGCAGTACATAGCTAAGGAA
AAGGATTTGCATGTGATTGGCATTGATAGAGGGGAGCGTAACTTGATATATGTGTCT
GTCATAGACACGTGTGGCAACATCGTCGAACAGAAATCATTCAACATAGTAAACGG
CTACGATTACCAAATTAAGCTGAAACAGCAAGAGGGTGCACGTCAAATTGCGCGTA
AAGAGTGGAAAGAAATTGGTAAAATCAAGGAAATTAAAGAAGGCTACTTGTCTCTT
GTTATACATGAAATTTCCAAGATGGTTATAAAGTATAACGCGATAATTGCTATGGAA
GACTTATCATACGGGTTTAAAAAGGGGAGGTTCAAGGTAGAGAGGCAGGTCTATCA
AAAGTTCGAGACGATGTTGATTAATAAACTAAACTATCTAGTGTTCAAAGATATCAG
CATTACGGAGAACGGGGGGCTACTGAAAGGATATCAACTAACGTACATTCCCGATA
AGTTAAAGAACGTTGGTCATCAATGTGGTTGCATCTTCTACGTGCCTGCTGCCTATA
CGTCCAAAATAGATCCAACTACTGGATTTGTTAACATCTTTAAATTCAAAGATTTAA
CCGTAGACGCCAAAAGGGAATTTATAAAAAAATTTGACAGCATCCGTTACGATAGC
GAAAAGAATCTGTTCTGTTTTACTTTCGACTACAATAATTTCATCACGCAAAATACG
GTAATGTCTAAGTCAAGTTGGAGCGTCTACACGTATGGAGTCAGGATCAAGAGGCG
TTTCGTAAATGGAAGATTCTCTAATGAGTCAGATACTATAGACATCACGAAAGATAT
GGAGAAAACCTTGGAGATGACGGATATTAACTGGCGTGATGGACACGATTTAAGAC
AGGACATTATTGACTATGAGATTGTGCAACACATCTTCGAAATATTCCGTCTAACAG
TCCAAATGAGGAATAGCCTAAGTGAATTGGAGGACCGTGATTACGATAGGCTTATA
AGTCCTGTCCTTAACGAAAACAATATTTTCTATGATAGTGCTAAGGCGGGGGACGCA
CTGCCTAAAGACGCAGATGCTAACGGGGCATACTGCATTGCGTTAAAGGGTCTGTAC
GAAATCAAGCAGATTACGGAAAACTGGAAAGAGGATGGCAAGTTTAGCAGAGATA
AGTTGAAGATAAGTAACAAAGATTGGTTTGACTTTATTCAGAATAAAAGGTATTTAA
AACGTCCGGCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGG
TAGCGGCGCAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAA
CGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 58
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAACGGCACTAATAATTTCCAGAATTTCATCGGCATTAGCAGCTTACAAAAGACGTT
GAGGAATGCCTTAATACCCACAGAAACTACTCAACAATTTATAGTGAAGAATGGGA
TAATTAAGGAAGACGAGTTGAGAGGTGAAAATAGGCAAATCTTGAAAGACATTATG
GATGACTACTACAGGGGCTTCATTAGTGAAACGTTGTCTTCAATAGATGACATTGAT
TGGACTTCTTTGTTTGAGAAGATGGAAATACAGTTAAAGAACGGCGACAATAAGGA
TACACTTATCAAAGAGCAAACAGAATATAGAAAAGCAATTCACAAAAAGTTTGCTA
ACGATGATAGGTTCAAGAACATGTTTAGCGCTAAACTAATATCAGACATCCTTCCCG
AGTTCGTTATTCATAACAATAACTATAGTGCAAGTGAAAAAGAGGAGAAGACACAG
GTGATTAAGCTGTTCTCCAGATTCGCGACTTCTTTCAAAGATTACTTCAAAAACAGA
GCCAACTGTTTTTCAGCTGACGATATCTCTAGTAGTAGTTGTCACCGTATAGTGAAC
GATAACGCTGAGATCTTCTTTAGCAATGCATTAGTGTATAGAAGGATAGTTAAGTCT
CTAAGCAATGATGATATCAATAAAATTTCCGGAGACATGAAGGACTCCCTAAAGGA
AATGTCCTTAGAAGAGATCTACTCATATGAGAAATACGGGGAATTTATTACGCAGG
AAGGGATCTCCTTTTACAATGACATATGCGGGAAGGTCAACTCTTTCATGAACTTAT
ACTGCCAAAAGAACAAGGAGAACAAGAATTTATATAAACTTCAGAAACTTCACAAA
CAAATACTGTGCATAGCCGATACCTCATATGAGGTTCCTTACAAATTTGAATCAGAT
GAAGAGGTATACCAATCCGTTAACGGCTTTCTTGACAATATTAGCTCAAAGCACATC
GTGGAGAGGTTGAGAAAGATTGGTGATAATTATAATGGCTACAATCTAGATAAGAT
ATATATTGTTAGCAAGTTCTACGAGTCTGTGTCCCAAAAAACATATAGGGATTGGGA
GACAATTAATACTGCTCTAGAAATCCATTACAACAACATCCTTCCTGGAAATGGCAA
GAGTAAGGCCGACAAAGTCAAGAAAGCAGTGAAAAATGATCTGCAAAAATCAATTA
CTGAGATAAACGAGCTAGTATCTAATTACAAGCTTTGTAGCGACGATAACATTAAGG
CAGAAACGTACATACACGAGATTAGTCACATCTTAAATAATTTTGAAGCCCAAGAA
CTGAAATATAACCCTGAGATACACCTTGTTGAATCCGAGTTAAAGGCGTCTGAACTA
AAAAACGTGTTAGACGTTATTATGAATGCCTTCCACTGGTGTAGCGTCTTTATGACT
GAGGAGTTGGTTGATAAGGATAATAACTTTTACGCTGAATTGGAAGAAATTTATGAC
GAAATCTATCCTGTTATTTCTCTATATAATTTGGTGAGAAATTACGTAACGCAAAAG
CCCTATAGTACGAAAAAAATAAAACTAAATTTCGGGATCCCTACCCTAGCCGACGGT
TGGTCTAAATCCAAGGAGTACTCAAACAATGCAATAATATTGATGAGGGACAACCT
GTACTACCTAGGCATATTTAATGCCAAAAATAAGCCCGATAAAAAGATTATAGAAG
GGAACACGTCAGAAAATAAAGGAGACTATAAGAAAATGATCTACAACCTTTTGCCC
GGCCCCAATAAAATGATCCCGAAGGTCTTCCTAAGTAGCAAGACTGGCGTAGAGAC
CTACAAACCATCTGCATACATTTTGGAGGGGTACAAGCAAAACAAGCACATAAAGA
GTAGTAAGGATTTTGACATTACATTCTGCCATGACTTAATTGACTACTTTAAAAATTG
CATCGCAATTCACCCTGAATGGAAAAATTTTGGATTTGATTTCTCTGATACTTCAACA
TATGAGGATATTTCAGGGTTCTACAGGGAGGTCGAACTACAGGGTTACAAAATAGA
CTGGACGTATATTTCTGAGAAAGATATAGATTTGCTTCAGGAAAAGGGTCAGCTATA
TCTGTTCCAGATATATAATAAGGACTTCTCCAAAAAGAGTACCGGAAATGATAATCT
GCACACAATGTACTTAAAAAACTTGTTCTCTGAGGAGAATCTAAAAGACATCGTACT
AAAACTTAACGGGGAGGCCGAAATTTTTTTTAGGAAGTCCAGCATCAAGAACCCGA
TTATTCATAAAAAAGGTAGCATTTTGGTGAACCGTACTTATGAGGCGGAAGAAAAA
GACCAATTCGGTAATATTCAAATCGTTAGAAAGAACATCCCTGAGAACATTTATCAG
GAACTATACAAATACTTTAACGACAAATCAGATAAGGAGCTTTCTGATGAGGCAGC
TAAATTGAAAAATGTAGTGGGACATCACGAAGCAGCCACTAACATAGTGAAGGACT
ACAGATACACATACGATAAGTACTTCCTGCACATGCCTATTACAATTAACTTTAAAG
CAAATAAAACAGGGTTTATTAACGACAGAATCTTACAGTATATTGCCAAAGAAAAG
GATCTGCATGTGATAGGAATAGACAGAGGAGAAAGAAACCTGATATACGTCTCCGT
GATTGATACATGTGGGAACATAGTAGAACAGAAGTCCTTTAACATTGTTAATGGGTA
CGATTATCAAATTAAATTAAAACAACAAGAAGGAGCACGTCAAATAGCTAGGAAAG
AATGGAAAGAGATAGGAAAAATTAAGGAAATTAAGGAGGGTTACCTGTCCCTTGTA
ATTCATGAAATATCCAAAATGGTAATTAAATATAACGCGATCATCGCGATGGAAGA
TCTAAGCTACGGGTTCAAAAAAGGCAGGTTTAAGGTGGAGAGGCAAGTTTACCAAA
AGTTCGAGACAATGTTGATTAATAAGTTAAACTACTTAGTTTTCAAAGATATCTCCA
TAACCGAGAATGGCGGGCTTTTAAAAGGGTACCAACTAACATATATCCCGGATAAA
TTGAAGAACGTTGGACACCAGTGTGGCTGCATATTTTATGTACCCGCTGCGTATACT
TCTAAAATTGACCCGACCACCGGGTTTGTAAACATATTCAAGTTTAAGGACCTAACA
GTTGACGCCAAACGTGAGTTCATCAAGAAGTTCGATAGTATAAGGTATGACTCTGAG
AAGAACCTTTTCTGCTTCACGTTTGACTATAATAATTTCATCACCCAAAATACAGTTA
TGTCAAAAAGCTCTTGGTCAGTATATACGTATGGCGTAAGGATTAAGCGTAGGTTCG
TGAACGGTAGATTTTCCAACGAGTCAGATACTATTGATATTACCAAGGATATGGAGA
AGACATTAGAAATGACAGATATAAATTGGAGGGATGGGCACGATCTAAGGCAAGAT
ATCATTGATTACGAAATTGTTCAGCACATATTCGAGATATTCCGTCTTACAGTACAA
ATGCGTAACAGCTTGTCTGAGTTGGAAGATCGTGACTATGACAGGTTGATATCACCG
GTCTTGAACGAGAACAATATATTCTACGACAGCGCTAAGGCGGGAGACGCTCTGCC
TAAAGACGCAGATGCCAATGGGGCGTACTGCATTGCCTTAAAAGGCTTATACGAGA
TTAAACAGATCACAGAGAACTGGAAAGAGGACGGCAAGTTTTCTAGAGATAAATTG
AAAATCTCAAACAAAGACTGGTTCGATTTCATCCAAAACAAAAGATACCTTAAACG
TCCGGCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGC
GGCGCAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTA
AGGTTATTCCGGGCTAA
SEQ ID NO: 59
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAATGGAACTAACAACTTCCAGAACTTTATCGGCATCTCTTCCCTCCAAAAGACACT
GAGAAATGCACTGATCCCAACCGAAACGACTCAACAATTTATTGTTAAGAACGGCA
TCATAAAAGAAGACGAGCTTCGCGGCGAGAACCGCCAGATACTTAAGGATATTATG
GACGATTATTACCGAGGCTTTATCAGCGAAACTCTTAGCTCTATTGATGATATCGAC
TGGACCTCCCTCTTCGAAAAAATGGAGATACAGCTCAAGAACGGCGATAATAAAGA
CACCTTGATAAAGGAACAGACTGAGTACAGGAAAGCGATCCACAAGAAATTCGCGA
ACGACGACAGGTTTAAAAACATGTTCTCTGCAAAATTGATATCCGACATCTTGCCGG
AATTTGTGATACACAACAATAACTATAGCGCTTCAGAGAAAGAAGAGAAGACCCAA
GTAATCAAGTTGTTCAGCCGCTTCGCAACGTCTTTTAAAGATTACTTTAAGAACCGG
GCCAATTGTTTCTCCGCGGATGATATTAGCTCATCAAGTTGCCATCGAATTGTCAAT
GATAATGCGGAGATCTTCTTCAGCAATGCGCTGGTCTACAGACGAATCGTAAAAAGT
CTTTCAAATGACGACATCAATAAGATTAGTGGAGATATGAAGGATTCCCTTAAGGA
AATGAGTCTTGAAGAAATATACTCATACGAAAAGTACGGGGAATTTATTACCCAGG
AGGGGATCTCCTTCTATAACGACATCTGTGGAAAAGTAAACTCATTCATGAACCTGT
ACTGTCAGAAAAACAAAGAAAACAAAAATCTGTATAAACTCCAAAAATTGCACAAG
CAAATATTGTGTATAGCGGACACATCATACGAGGTTCCATATAAGTTCGAAAGTGAT
GAAGAAGTCTACCAATCAGTGAATGGGTTTCTGGACAACATTAGTTCCAAGCACATA
GTTGAACGACTGCGAAAGATTGGTGACAATTACAACGGCTATAATTTGGACAAGAT
TTATATAGTTAGCAAATTTTATGAATCCGTATCACAAAAGACTTATAGAGACTGGGA
AACAATCAACACGGCACTTGAGATCCATTATAACAATATTCTTCCAGGGAACGGCA
AAAGCAAGGCTGATAAGGTAAAAAAGGCCGTTAAGAATGATCTTCAAAAATCCATA
ACGGAGATCAACGAACTTGTAAGTAACTACAAATTGTGCTCTGACGACAATATAAA
GGCTGAAACGTATATTCACGAGATTAGCCATATCCTGAATAACTTTGAGGCCCAAGA
ACTCAAGTATAACCCGGAAATACATTTGGTAGAAAGCGAGCTTAAAGCGAGTGAGC
TGAAAAACGTCCTCGATGTGATCATGAATGCTTTCCACTGGTGTAGTGTCTTTATGA
CTGAGGAGTTGGTTGATAAAGACAATAATTTCTACGCTGAACTGGAAGAAATTTACG
ACGAAATCTATCCAGTGATCTCCCTCTATAACCTCGTTCGAAACTACGTGACGCAGA
AACCTTATTCTACAAAGAAAATTAAGTTGAACTTCGGCATTCCTACACTTGCTGACG
GATGGTCCAAATCCAAAGAGTACTCAAACAACGCAATCATCCTCATGCGGGATAAC
CTTTATTATTTGGGCATTTTCAACGCCAAAAACAAACCTGATAAAAAGATAATTGAA
GGCAATACGAGTGAGAACAAGGGCGACTACAAAAAAATGATATATAACTTGTTGCC
AGGCCCCAACAAGATGATTCCTAAAGTTTTTCTGTCTTCTAAGACTGGAGTTGAAAC
TTACAAACCCTCCGCCTACATTCTTGAAGGGTATAAACAGAATAAGCACATAAAGTC
CTCAAAGGATTTCGACATTACGTTTTGCCATGACCTCATCGACTATTTCAAGAACTGT
ATCGCCATACATCCGGAGTGGAAGAATTTTGGATTTGATTTCTCCGACACATCTACC
TATGAAGACATAAGCGGTTTCTACCGGGAGGTCGAGCTTCAGGGCTATAAGATAGA
TTGGACATACATTAGTGAAAAAGATATCGATCTTCTGCAAGAAAAGGGACAACTTT
ACCTTTTTCAGATTTATAATAAAGACTTTTCAAAAAAGTCCACAGGGAACGATAATC
TGCACACCATGTATCTCAAGAATCTGTTTAGTGAAGAAAACCTTAAAGACATAGTTT
TGAAGCTTAACGGAGAGGCTGAGATTTTTTTTAGAAAGTCCTCAATTAAAAACCCTA
TAATACACAAGAAAGGCTCTATTCTTGTTAACAGGACATATGAAGCCGAGGAGAAA
GATCAGTTTGGCAATATCCAGATTGTTCGCAAGAATATCCCGGAAAATATATATCAG
GAGCTGTATAAATACTTTAACGACAAGAGCGACAAGGAGCTGAGTGACGAGGCCGC
GAAGCTTAAGAATGTAGTAGGTCACCACGAAGCAGCCACCAATATCGTCAAAGACT
ATAGGTACACGTACGACAAGTACTTTTTGCACATGCCTATAACTATAAACTTCAAAG
CTAATAAAACTGGGTTTATTAATGACAGGATTCTCCAATACATCGCTAAAGAGAAGG
ATCTGCATGTAATTGGCATAGACAGAGGTGAGAGAAACTTGATATATGTCAGCGTA
ATAGACACATGTGGCAATATCGTGGAACAGAAGTCTTTTAACATCGTCAATGGTTAC
GACTACCAAATTAAGTTGAAACAGCAGGAAGGCGCACGACAGATCGCACGAAAGG
AATGGAAAGAGATAGGCAAAATAAAAGAAATAAAGGAGGGCTATCTCAGTCTCGTT
ATACACGAAATTTCAAAAATGGTTATTAAGTACAATGCAATCATAGCGATGGAGGA
TCTCAGTTATGGGTTCAAAAAGGGTCGGTTTAAAGTTGAGCGCCAAGTGTACCAAAA
GTTCGAGACAATGCTGATTAACAAGCTGAACTACCTCGTCTTCAAAGATATAAGTAT
TACGGAGAACGGTGGCCTTCTTAAAGGCTATCAACTTACTTACATCCCGGACAAGCT
CAAAAACGTAGGGCACCAATGCGGGTGTATTTTCTATGTGCCTGCGGCATATACGTC
AAAGATTGACCCAACCACAGGATTCGTAAACATATTCAAGTTTAAGGACCTCACCGT
TGATGCGAAAAGGGAGTTCATTAAAAAATTTGATTCTATTCGATATGATAGTGAGAA
AAATCTCTTTTGTTTCACATTTGACTATAATAATTTTATTACTCAGAATACTGTCATG
AGCAAGTCATCTTGGTCAGTGTACACATACGGGGTGCGGATCAAACGCAGGTTCGTC
AATGGTCGCTTCTCAAACGAATCAGACACCATTGACATCACAAAGGACATGGAAAA
AACCCTTGAGATGACCGACATTAATTGGCGCGATGGTCATGATCTGCGGCAAGACAT
CATAGACTACGAAATCGTCCAACACATCTTTGAGATCTTTCGCTTGACGGTCCAAAT
GCGGAACTCCCTGTCCGAGCTCGAGGATAGAGATTATGATCGGCTGATATCTCCCGT
GCTTAATGAAAATAACATCTTCTACGACTCCGCCAAGGCGGGTGATGCCCTGCCGAA
GGATGCGGATGCTAATGGCGCTTATTGCATTGCTCTTAAGGGGCTCTATGAGATAAA
GCAGATCACGGAAAACTGGAAAGAAGACGGTAAGTTTAGTAGAGACAAGCTGAAG
ATCTCAAATAAAGACTGGTTTGATTTCATACAGAACAAGCGGTACCTGAAACGTCCG
GCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCG
CAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGT
TATTCCGGGCTAA
SEQ ID NO: 60
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
CAATGGCACTAACAATTTTCAGAATTTCATCGGCATTTCAAGTCTGCAAAAAACTCT
GAGGAATGCTTTGATCCCTACTGAAACCACTCAGCAATTTATAGTCAAGAACGGTAT
AATTAAAGAAGATGAACTCAGGGGTGAAAATAGACAAATACTCAAGGACATTATGG
ATGACTATTATAGAGGCTTCATCTCAGAGACTCTCTCATCAATAGATGATATCGATT
GGACTAGCCTTTTCGAGAAAATGGAGATTCAGTTGAAAAATGGTGATAACAAAGAT
ACGTTGATAAAGGAACAGACCGAGTACAGGAAAGCCATTCATAAGAAATTTGCTAA
TGACGATAGATTTAAGAATATGTTTAGTGCAAAACTGATTAGTGACATTCTGCCGGA
GTTCGTTATCCATAATAATAACTACTCTGCATCCGAAAAGGAGGAAAAGACGCAAG
TTATTAAACTGTTCAGCCGCTTCGCCACAAGCTTCAAGGACTACTTCAAAAATAGAG
CCAACTGCTTTTCTGCCGACGATATATCATCATCTTCATGCCATCGGATCGTTAACGA
TAACGCCGAGATATTCTTCAGCAACGCCCTTGTATATCGAAGAATAGTCAAAAGTCT
GAGTAATGATGATATTAATAAAATTAGCGGTGATATGAAAGACTCCCTGAAGGAAA
TGTCACTGGAGGAAATTTATAGTTACGAAAAGTACGGCGAATTCATTACTCAAGAA
GGCATATCCTTCTATAACGACATTTGCGGAAAGGTCAACTCATTCATGAACCTTTAT
TGCCAGAAGAATAAGGAGAATAAAAATCTTTACAAATTGCAAAAACTTCACAAACA
AATTCTTTGCATCGCGGATACGTCCTACGAAGTTCCTTACAAATTTGAATCCGATGA
GGAAGTGTATCAGAGTGTCAATGGATTTTTGGATAATATCTCTTCAAAACATATTGT
GGAGAGATTGCGCAAAATAGGTGATAACTACAATGGCTACAACCTGGACAAGATTT
ATATTGTTAGCAAGTTCTATGAAAGTGTCAGTCAAAAGACCTACAGAGATTGGGAG
ACAATCAACACGGCGCTCGAAATACACTACAATAACATCCTCCCCGGCAATGGGAA
GAGTAAAGCCGATAAGGTTAAAAAAGCTGTTAAGAACGACCTCCAGAAATCCATCA
CGGAAATAAACGAGCTGGTTTCCAACTATAAGCTGTGTAGCGATGATAATATTAAG
GCTGAGACATATATACATGAGATCAGCCACATTCTCAACAATTTCGAGGCACAGGA
ACTCAAATACAATCCCGAGATTCACTTGGTGGAAAGTGAGTTGAAGGCGTCAGAGC
TTAAGAATGTACTTGACGTAATAATGAATGCTTTTCATTGGTGCTCCGTGTTCATGAC
TGAGGAACTCGTGGATAAGGATAATAACTTTTATGCGGAGTTGGAAGAGATATACG
ATGAAATATACCCGGTTATCTCACTGTATAATCTGGTCAGAAATTACGTGACCCAAA
AGCCTTATAGTACAAAAAAAATAAAGTTGAACTTCGGTATTCCGACATTGGCAGATG
GTTGGTCCAAAAGCAAAGAATACTCTAATAACGCCATTATATTGATGCGAGACAATT
TGTATTACCTTGGGATCTTTAACGCGAAAAACAAACCGGATAAGAAGATCATCGAA
GGTAATACATCTGAGAATAAGGGGGATTACAAGAAGATGATTTATAATCTGTTGCC
GGGGCCAAACAAGATGATTCCGAAGGTCTTTCTGTCATCTAAGACAGGAGTAGAGA
CCTACAAACCTTCTGCGTACATTTTGGAAGGCTACAAACAGAACAAGCATATAAAAT
CTAGCAAGGACTTTGATATCACGTTTTGTCATGATCTGATAGATTATTTCAAAAACT
GCATCGCTATACATCCTGAGTGGAAGAATTTCGGCTTTGACTTTTCTGACACCAGCA
CATACGAAGACATCTCAGGTTTCTACCGGGAAGTCGAGCTCCAGGGGTACAAGATT
GACTGGACATATATAAGTGAAAAAGACATCGACCTCCTCCAAGAGAAGGGCCAACT
TTACCTGTTCCAGATCTATAACAAAGACTTTTCTAAAAAGTCCACGGGTAACGACAA
CTTGCACACTATGTATCTGAAAAACTTGTTCTCTGAAGAGAACCTCAAGGACATCGT
CCTGAAGCTTAACGGGGAGGCGGAGATCTTCTTTAGAAAGTCCTCTATCAAAAATCC
CATTATCCATAAAAAGGGCTCTATACTCGTTAATAGGACATATGAAGCGGAGGAAA
AAGATCAATTTGGGAACATCCAGATCGTCCGGAAAAATATACCTGAGAATATCTATC
AAGAGCTGTACAAGTATTTTAATGATAAGTCAGACAAAGAGCTCAGTGATGAGGCG
GCAAAGCTCAAGAACGTGGTGGGGCATCATGAAGCTGCGACGAACATTGTCAAAGA
TTATAGATACACTTACGATAAATACTTCCTCCACATGCCGATAACGATTAACTTCAA
AGCCAATAAGACGGGGTTTATAAATGATCGGATCCTTCAGTACATTGCGAAAGAGA
AAGACCTCCATGTGATCGGAATTGACCGAGGAGAAAGGAATCTGATTTACGTGTCC
GTGATTGATACTTGCGGGAATATAGTCGAGCAAAAGAGTTTCAACATAGTCAACGG
GTATGACTATCAGATAAAGCTCAAACAGCAGGAAGGTGCGAGGCAAATTGCGCGCA
AAGAGTGGAAGGAGATAGGCAAGATTAAAGAAATCAAGGAAGGTTATCTCAGCTTG
GTGATCCATGAAATATCTAAGATGGTTATAAAGTACAATGCCATAATAGCCATGGA
GGATCTTTCCTACGGGTTTAAGAAGGGCCGATTTAAAGTGGAGCGACAAGTTTACCA
GAAGTTCGAAACCATGTTGATTAACAAACTTAACTATTTGGTGTTCAAGGATATAAG
TATAACCGAAAACGGCGGTTTGCTTAAGGGTTATCAGCTCACGTATATTCCTGATAA
ACTTAAAAACGTTGGACACCAGTGTGGATGTATCTTCTACGTGCCAGCCGCTTACAC
TAGTAAGATAGATCCTACCACGGGGTTTGTGAATATTTTTAAGTTTAAAGACTTGAC
AGTCGACGCCAAAAGGGAATTTATAAAAAAGTTTGATTCTATCCGCTACGATAGTGA
AAAAAATCTCTTTTGCTTTACTTTCGACTATAACAACTTCATTACGCAGAACACTGTC
ATGAGTAAGTCCAGCTGGAGCGTCTACACATATGGCGTCCGAATTAAACGACGATTT
GTAAACGGGCGGTTTTCAAACGAATCTGACACGATAGACATTACCAAGGATATGGA
GAAGACACTTGAGATGACCGACATAAACTGGCGGGACGGTCACGATCTTCGGCAGG
ACATAATTGATTACGAAATCGTCCAGCATATATTCGAAATATTTCGACTTACAGTGC
AAATGCGGAACAGTCTCTCTGAACTGGAAGATCGCGATTATGACCGGTTGATTTCTC
CGGTCCTCAATGAAAATAACATATTTTATGATAGTGCTAAGGCAGGTGATGCGTTGC
CAAAGGATGCAGACGCTAATGGTGCCTATTGTATCGCGCTCAAGGGATTGTACGAG
ATAAAGCAAATTACGGAGAACTGGAAGGAGGATGGTAAGTTTAGCCGAGACAAGTT
GAAGATTAGCAATAAAGACTGGTTTGATTTTATCCAAAACAAGAGGTACCTGAAAC
GTCCGGCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAG
CGGCGCAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGT
AAGGTTATTCCGGGCTAA
SEQ ID NO: 61
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAACGGAACTAATAACTTTCAAAATTTCATAGGTATTTCAAGCTTGCAGAAGACCCT
GAGGAATGCCCTGATTCCAACCGAGACAACGCAGCAGTTCATAGTCAAAAATGGCA
TTATTAAGGAAGATGAGCTGCGGGGGGAAAACCGACAGATACTCAAGGATATTATG
GACGACTATTACCGGGGATTTATCTCAGAAACGCTGAGCAGTATTGATGACATCGAT
TGGACCAGTCTTTTCGAGAAAATGGAAATTCAACTTAAGAATGGTGACAATAAAGA
CACTCTCATAAAGGAGCAAACTGAATACCGAAAAGCCATACACAAAAAGTTTGCCA
ACGATGACCGCTTTAAAAACATGTTTTCAGCTAAGCTCATTAGCGACATTCTCCCCG
AGTTTGTGATTCATAACAATAACTATAGCGCATCCGAGAAGGAGGAAAAAACCCAA
GTTATCAAATTGTTCAGTAGATTCGCTACGAGCTTTAAAGATTACTTTAAAAACCGG
GCTAACTGCTTCAGTGCAGACGATATCAGCTCCTCATCCTGTCATCGCATCGTCAAT
GATAATGCTGAGATCTTCTTTTCTAATGCACTGGTTTACCGCAGGATAGTTAAGTCTC
TTAGTAACGACGACATCAACAAGATATCAGGAGATATGAAGGATTCCCTTAAAGAA
ATGAGTCTCGAGGAGATATATTCTTATGAAAAATACGGCGAATTTATTACCCAAGAG
GGCATTAGTTTCTATAATGACATATGCGGAAAAGTTAATAGTTTTATGAATCTCTATT
GTCAGAAGAATAAGGAGAATAAGAACCTCTACAAATTGCAGAAGTTGCACAAGCAA
ATTCTGTGTATCGCGGACACCTCTTACGAGGTCCCATATAAGTTCGAGAGTGATGAA
GAAGTATACCAGAGCGTTAATGGGTTCCTGGACAACATCTCAAGTAAACACATAGT
CGAAAGGCTCCGAAAGATCGGTGATAACTATAACGGATATAATTTGGATAAAATTT
ATATAGTTAGCAAATTTTACGAGAGCGTCAGTCAGAAGACCTACCGGGACTGGGAG
ACCATAAACACAGCGCTGGAAATACATTATAACAACATACTGCCTGGGAACGGTAA
GTCAAAGGCAGACAAGGTTAAAAAGGCTGTGAAGAATGACCTGCAAAAATCAATTA
CAGAAATAAATGAGTTGGTAAGTAATTACAAACTTTGCAGCGATGATAATATAAAG
GCAGAGACGTACATACATGAAATATCTCATATCCTCAACAATTTCGAAGCCCAAGA
ACTGAAGTACAACCCGGAAATTCATCTTGTAGAGTCTGAGTTGAAGGCCTCCGAATT
GAAAAACGTTCTTGACGTAATTATGAATGCCTTCCACTGGTGCTCAGTATTCATGAC
GGAAGAGCTCGTGGATAAAGACAACAATTTTTACGCTGAACTGGAAGAAATATATG
ACGAGATTTACCCCGTAATTTCACTCTACAACTTGGTACGAAATTACGTTACCCAAA
AGCCATACTCAACAAAAAAAATTAAACTGAACTTCGGGATACCCACCCTCGCAGAT
GGATGGTCAAAGTCCAAAGAGTACAGTAACAATGCAATTATCCTGATGCGAGACAA
CCTTTATTACCTCGGGATTTTCAACGCTAAAAATAAACCTGATAAAAAAATAATTGA
GGGTAATACCTCTGAAAACAAGGGGGATTATAAAAAGATGATATACAATCTGCTGC
CTGGCCCGAACAAAATGATTCCTAAAGTCTTCTTGTCTTCCAAGACTGGAGTCGAAA
CCTACAAGCCAAGTGCTTATATACTCGAAGGGTACAAACAAAATAAGCACATAAAA
TCCAGCAAGGATTTTGATATTACATTCTGCCACGATTTGATTGATTATTTTAAGAACT
GTATAGCCATCCACCCAGAATGGAAGAATTTTGGTTTTGATTTTAGCGATACCTCAA
CATATGAGGATATCTCTGGCTTTTACCGCGAGGTAGAACTGCAAGGTTATAAGATCG
ATTGGACTTATATTTCTGAAAAGGACATAGATCTCCTGCAAGAGAAAGGGCAACTTT
ATTTGTTTCAAATATACAACAAAGATTTTAGTAAGAAGAGTACTGGCAATGATAACC
TTCACACTATGTATCTGAAGAACCTTTTTTCTGAGGAGAACTTGAAGGACATAGTCC
TTAAACTCAATGGGGAAGCTGAAATATTCTTTCGCAAAAGCTCCATTAAAAACCCGA
TCATTCATAAAAAGGGTTCCATCTTGGTAAACCGCACATACGAGGCGGAAGAAAAA
GATCAGTTCGGAAATATCCAGATCGTAAGGAAGAATATCCCCGAAAATATATACCA
AGAGCTTTACAAATATTTTAACGATAAGTCAGACAAGGAACTGTCAGACGAAGCAG
CCAAGTTGAAGAATGTCGTAGGGCACCACGAAGCAGCTACAAACATAGTTAAAGAT
TATCGGTACACCTACGATAAATATTTCCTGCATATGCCAATAACCATAAACTTCAAA
GCCAACAAAACAGGGTTCATCAATGACCGAATACTTCAGTATATAGCCAAGGAAAA
AGACCTGCATGTTATAGGAATAGATAGAGGTGAGCGCAACTTGATATATGTCAGCG
TGATAGACACCTGCGGAAATATCGTCGAGCAAAAAAGTTTCAACATTGTTAATGGCT
ACGATTACCAAATTAAATTGAAGCAGCAAGAGGGGGCTCGGCAAATCGCGCGAAAG
GAATGGAAAGAAATCGGGAAGATTAAAGAAATTAAAGAGGGCTACCTGTCTCTTGT
AATTCACGAAATATCTAAGATGGTCATCAAGTATAATGCCATTATTGCGATGGAAGA
TCTGTCCTACGGATTTAAGAAAGGCAGGTTTAAAGTCGAAAGGCAGGTGTACCAGA
AATTCGAGACCATGCTGATTAATAAGCTCAACTATCTCGTATTTAAGGATATTTCTAT
AACTGAAAATGGAGGGCTTCTCAAAGGATATCAACTCACATACATACCTGATAAGC
TGAAGAACGTAGGCCACCAGTGTGGATGCATATTCTATGTACCAGCTGCATACACAA
GCAAGATCGATCCAACTACTGGGTTTGTCAATATCTTCAAATTTAAGGACTTGACGG
TCGATGCCAAACGGGAGTTCATCAAAAAGTTTGATAGTATTCGATATGATAGTGAGA
AGAACTTGTTTTGCTTCACATTTGACTACAACAATTTCATAACGCAAAATACGGTTA
TGTCTAAATCCTCATGGAGCGTCTACACTTACGGAGTGAGGATAAAGCGGCGCTTCG
TAAATGGCAGGTTTAGCAATGAATCCGACACGATTGACATAACCAAGGATATGGAG
AAAACCCTCGAGATGACCGATATAAATTGGCGGGATGGACACGATCTGCGACAAGA
CATAATCGATTATGAAATCGTGCAGCACATATTTGAGATATTCAGGCTTACGGTCCA
AATGAGAAATTCCCTTTCCGAACTTGAAGACCGCGATTACGACCGACTGATAAGCCC
CGTTCTGAACGAAAATAACATCTTCTACGACAGCGCTAAAGCGGGAGACGCGCTGC
CGAAAGATGCGGACGCAAATGGAGCCTATTGTATCGCCTTGAAAGGGTTGTACGAG
ATCAAACAGATAACCGAGAATTGGAAGGAGGATGGGAAGTTTAGTCGAGACAAACT
TAAAATAAGCAACAAGGACTGGTTCGACTTTATTCAAAACAAACGATATCTCAAAC
GTCCGGCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAG
CGGCGCAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGT
AAGGTTATTCCGGGCTAA
SEQ ID NO: 62
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAATGGTACTAACAATTTTCAAAACTTTATCGGCATCTCTTCACTTCAGAAAACTCTT
CGGAACGCCCTTATACCGACGGAGACAACGCAGCAGTTTATAGTTAAAAACGGGAT
CATTAAAGAAGATGAACTCAGAGGGGAAAACAGGCAAATATTGAAGGACATTATGG
ACGATTACTACCGGGGGTTTATTTCAGAGACCCTTTCATCTATTGATGACATAGATT
GGACCTCCCTTTTCGAGAAAATGGAGATACAATTGAAAAACGGCGACAATAAAGAT
ACACTTATCAAGGAACAAACTGAGTATCGCAAGGCGATTCACAAGAAGTTTGCGAA
TGACGATCGCTTTAAGAATATGTTTTCTGCGAAGCTCATAAGTGACATTCTGCCTGA
ATTTGTCATTCATAACAACAATTATTCTGCTAGCGAAAAAGAGGAAAAAACTCAAGT
CATTAAGCTTTTTAGCAGGTTCGCTACTAGTTTTAAAGACTATTTTAAGAACCGGGC
GAATTGCTTTAGCGCTGACGACATATCATCCTCATCCTGTCATCGCATAGTCAATGA
TAATGCAGAAATATTCTTTTCTAATGCGCTCGTGTATCGGAGAATAGTGAAAAGCCT
CTCTAACGATGACATTAACAAAATAAGCGGCGATATGAAGGATAGTCTGAAGGAAA
TGTCCCTCGAAGAAATATACTCATACGAGAAGTACGGAGAATTTATCACCCAGGAA
GGAATTAGTTTTTACAACGACATCTGTGGTAAGGTTAACTCTTTTATGAATCTGTATT
GTCAAAAGAATAAAGAAAATAAAAATCTTTATAAGCTCCAAAAGCTTCACAAACAA
ATCTTGTGCATTGCGGATACGTCATACGAAGTACCTTACAAATTTGAAAGCGACGAA
GAGGTGTATCAGTCAGTGAATGGGTTCCTTGACAATATTTCTAGCAAACATATTGTG
GAGCGACTTCGAAAGATCGGTGATAATTACAATGGCTATAATTTGGATAAAATTTAC
ATAGTTAGTAAGTTTTATGAATCCGTCTCACAAAAGACGTACCGAGATTGGGAGACC
ATCAACACTGCTCTGGAGATTCATTACAATAATATATTGCCTGGGAATGGGAAGTCA
AAGGCCGACAAGGTTAAAAAAGCCGTAAAAAACGATCTTCAAAAGTCCATTACCGA
GATAAATGAACTTGTATCCAACTATAAGTTGTGCTCTGACGATAATATTAAAGCAGA
AACGTATATCCACGAAATAAGTCACATCCTGAACAACTTCGAAGCTCAAGAGCTCA
AGTATAATCCTGAAATTCATCTCGTCGAAAGCGAGCTGAAAGCATCCGAGTTGAAG
AATGTGCTTGATGTGATCATGAACGCATTCCATTGGTGCAGTGTGTTCATGACCGAA
GAACTTGTAGACAAAGACAACAACTTCTACGCTGAATTGGAAGAGATTTACGATGA
AATTTACCCCGTGATATCCCTCTATAATCTGGTAAGAAATTACGTCACGCAAAAACC
ATACAGTACCAAGAAAATAAAGCTCAACTTTGGTATTCCGACGTTGGCAGATGGGT
GGAGTAAGAGCAAGGAGTATTCTAACAATGCAATCATCCTCATGCGCGACAATTTGT
ATTATCTGGGGATCTTCAACGCGAAAAATAAGCCCGACAAAAAGATAATAGAAGGC
AATACGTCCGAGAACAAAGGGGACTATAAGAAAATGATTTATAACCTTCTTCCAGG
ACCCAACAAGATGATCCCAAAGGTTTTCTTGAGTTCAAAAACCGGCGTAGAAACTTA
TAAACCGTCCGCCTACATTCTGGAAGGGTACAAGCAAAACAAGCACATTAAGTCAT
CTAAGGATTTCGACATTACTTTTTGTCATGATTTGATAGACTACTTCAAAAATTGTAT
AGCGATACATCCGGAATGGAAAAATTTTGGGTTCGATTTTTCCGACACAAGTACTTA
TGAAGACATCTCAGGGTTTTATAGGGAAGTTGAACTGCAAGGTTACAAAATAGACT
GGACTTATATTAGTGAGAAGGACATTGATTTGCTCCAGGAAAAGGGTCAATTGTATC
TGTTCCAGATATATAACAAGGATTTCTCTAAAAAATCTACAGGTAACGACAATCTCC
ACACGATGTACCTCAAGAATCTCTTCAGCGAAGAGAATTTGAAGGATATCGTACTTA
AGCTCAATGGAGAAGCGGAAATATTCTTCAGAAAGTCCAGCATTAAGAATCCTATA
ATTCACAAGAAAGGGTCAATTCTCGTAAACCGGACTTATGAGGCCGAAGAAAAAGA
TCAGTTTGGTAACATTCAGATTGTACGGAAAAACATTCCCGAGAACATCTATCAAGA
ACTGTATAAATACTTTAATGATAAATCCGACAAGGAACTTTCTGACGAGGCTGCAAA
ATTGAAGAACGTAGTGGGACACCATGAGGCCGCAACCAATATAGTAAAGGATTACA
GATACACTTATGATAAGTATTTCCTCCATATGCCGATCACGATTAATTTCAAGGCGA
ATAAAACCGGCTTCATTAACGATCGCATTTTGCAATATATTGCGAAGGAAAAGGATT
TGCACGTGATAGGTATAGACCGGGGTGAACGAAACTTGATTTACGTCTCTGTGATCG
ACACATGCGGAAATATAGTTGAACAGAAGTCCTTTAATATTGTGAATGGTTACGACT
ACCAGATAAAATTGAAGCAACAGGAGGGCGCAAGACAGATAGCTCGCAAAGAGTG
GAAGGAAATCGGCAAGATCAAAGAAATAAAGGAGGGTTATCTTTCCCTGGTAATTC
ATGAAATTAGCAAGATGGTTATTAAGTATAATGCTATAATAGCTATGGAGGACCTTT
CCTATGGGTTCAAGAAAGGTCGCTTCAAAGTGGAGCGACAAGTGTATCAAAAGTTC
GAGACTATGTTGATAAATAAATTGAATTATTTGGTTTTTAAAGACATTTCAATAACT
GAGAACGGGGGTCTCTTGAAGGGGTACCAATTGACTTATATTCCGGACAAGTTGAA
GAATGTCGGACACCAGTGTGGTTGCATTTTCTACGTGCCTGCCGCTTACACCTCAAA
AATCGATCCGACCACTGGTTTTGTAAATATATTTAAATTCAAAGATCTCACCGTTGA
TGCCAAACGGGAGTTTATCAAAAAATTCGATTCCATTCGCTACGACTCTGAGAAAAA
CCTTTTTTGTTTCACGTTCGATTATAACAACTTTATAACCCAAAATACTGTAATGTCC
AAGTCAAGTTGGTCTGTCTATACTTACGGAGTAAGGATCAAGCGCCGCTTCGTTAAT
GGGAGATTCTCAAACGAGTCTGATACCATAGACATAACTAAAGACATGGAAAAAAC
CCTGGAAATGACGGACATCAATTGGCGAGACGGGCATGATCTTCGACAGGACATAA
TAGATTACGAAATTGTTCAACACATTTTCGAGATATTTCGACTTACGGTTCAGATGA
GGAATTCCCTTTCCGAATTGGAAGACCGGGATTATGATCGACTTATATCTCCCGTGC
TCAATGAAAACAATATTTTTTATGATTCAGCGAAAGCTGGGGACGCGCTGCCAAAA
GATGCCGATGCCAATGGAGCATACTGTATCGCCCTGAAGGGTTTGTATGAGATTAAG
CAAATTACTGAAAACTGGAAGGAAGATGGCAAGTTTTCTAGAGATAAGCTTAAGAT
TAGCAATAAGGACTGGTTTGACTTCATTCAAAATAAAAGGTATCTTAAACGTCCGGC
AGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCA
GGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTA
TTCCGGGCTAA
SEQ ID NO: 63
ATGGGCCATCATCATCATCATCACAGCAGCGGCGTCGATCTGGGTACCGAGAATTTG
TATTTCCAGAGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAA
TAATGGAACAAATAATTTTCAAAATTTTATTGGTATCAGTTCATTGCAAAAGACTTT
GAGAAATGCTTTGATCCCGACTGAGACCACACAGCAGTTCATCGTCAAAAATGGCA
TAATCAAGGAAGACGAACTTAGGGGTGAGAATAGACAAATATTGAAGGACATCATG
GATGACTATTATAGGGGGTTCATTTCCGAAACGCTCAGTAGTATTGATGACATTGAC
TGGACTAGTCTTTTCGAGAAAATGGAAATTCAGCTTAAGAACGGGGACAATAAAGA
CACGCTGATCAAGGAGCAAACGGAATATAGGAAGGCGATCCATAAAAAATTCGCGA
ATGATGATCGGTTTAAAAACATGTTTAGTGCCAAGTTGATCAGCGACATACTGCCCG
AATTCGTGATCCACAACAATAATTACAGCGCCTCCGAAAAGGAGGAAAAAACTCAG
GTCATTAAATTGTTTAGCCGATTCGCAACGAGTTTCAAAGATTATTTTAAGAACCGG
GCCAACTGTTTTTCAGCGGATGATATTAGCTCCAGCAGCTGCCATCGCATAGTAAAT
GATAACGCTGAAATCTTTTTTAGCAACGCACTTGTCTACCGGAGGATTGTAAAATCA
CTGTCAAATGATGACATTAACAAAATATCTGGAGATATGAAGGACTCACTCAAAGA
AATGAGCCTGGAAGAAATATATTCATACGAAAAATACGGGGAGTTTATTACCCAGG
AAGGTATCAGTTTTTATAATGATATATGTGGAAAAGTTAATTCATTTATGAATCTTTA
CTGTCAAAAAAATAAGGAGAACAAGAATTTGTACAAGCTCCAAAAACTTCATAAAC
AGATTCTGTGCATCGCAGACACAAGTTATGAGGTACCGTACAAATTTGAGAGCGAC
GAAGAAGTTTATCAGAGTGTGAATGGTTTCCTGGACAATATCTCTTCTAAACACATT
GTTGAGAGGCTTAGGAAGATCGGTGATAATTATAACGGCTATAATCTGGACAAAAT
TTATATTGTATCAAAGTTTTATGAATCAGTCTCTCAAAAGACGTATCGGGATTGGGA
AACAATTAACACGGCTCTGGAGATCCACTACAATAACATTCTGCCCGGCAACGGGA
AGAGCAAAGCTGATAAGGTCAAGAAGGCAGTCAAGAACGACCTTCAGAAGAGCAT
AACAGAAATTAACGAATTGGTCAGTAACTACAAACTGTGTAGTGATGACAACATAA
AAGCCGAAACATACATCCATGAAATAAGCCATATCCTGAATAACTTCGAAGCCCAA
GAACTTAAATACAATCCCGAGATTCATCTTGTCGAATCAGAACTCAAGGCGTCCGAG
CTCAAAAATGTCCTTGACGTGATAATGAATGCCTTCCACTGGTGCAGCGTATTCATG
ACGGAGGAGTTGGTAGATAAAGACAACAACTTTTATGCCGAATTGGAAGAGATTTA
TGATGAGATTTACCCCGTTATTTCTCTGTACAACTTGGTTCGAAACTACGTAACACA
AAAACCATACTCAACCAAAAAGATCAAACTCAATTTTGGCATACCTACATTGGCTGA
TGGTTGGTCCAAGTCAAAGGAATATAGCAATAATGCAATAATTCTCATGCGAGATA
ACTTGTATTATTTGGGGATCTTTAACGCTAAGAACAAACCAGATAAAAAGATAATCG
AGGGGAACACAAGTGAGAACAAGGGTGATTACAAAAAAATGATTTACAATCTGCTT
CCTGGGCCTAACAAAATGATTCCGAAGGTGTTTCTTAGCTCTAAAACTGGAGTGGAG
ACGTATAAGCCTTCCGCGTACATTCTCGAAGGCTACAAGCAAAATAAGCATATCAA
GTCCAGTAAGGACTTCGACATCACTTTTTGCCACGATCTCATCGATTACTTTAAGAA
CTGTATCGCAATACACCCCGAGTGGAAAAACTTTGGTTTTGATTTTTCAGACACTAG
TACCTACGAGGACATTTCCGGCTTCTATCGAGAAGTCGAACTCCAGGGCTACAAAAT
CGATTGGACGTACATTTCTGAGAAGGACATCGACTTGCTCCAAGAGAAAGGTCAAC
TTTACCTCTTCCAAATTTACAATAAAGACTTTTCAAAGAAGAGCACCGGTAATGACA
ACTTGCATACCATGTATCTGAAGAACCTGTTTTCTGAGGAGAACCTCAAGGATATTG
TATTGAAGTTGAATGGCGAAGCAGAAATATTTTTCCGAAAGTCATCTATCAAGAACC
CCATTATACACAAAAAAGGCTCTATCCTGGTGAACCGGACTTACGAGGCAGAGGAG
AAGGATCAATTCGGAAACATACAGATAGTCCGCAAAAACATCCCTGAGAATATCTA
TCAGGAACTCTATAAGTACTTCAATGATAAATCAGACAAGGAGCTTAGCGACGAAG
CAGCTAAACTTAAAAACGTGGTTGGCCATCACGAGGCCGCTACCAACATAGTCAAA
GACTACCGCTATACTTATGACAAGTACTTTTTGCACATGCCCATAACAATTAATTTCA
AAGCTAACAAAACAGGGTTTATAAATGACAGAATCCTCCAATACATCGCCAAAGAG
AAGGACCTCCATGTAATCGGGATTGATAGAGGCGAACGGAACTTGATTTACGTTAGT
GTCATTGATACCTGTGGTAACATTGTCGAACAAAAGTCATTCAACATAGTCAATGGA
TATGATTATCAGATAAAACTCAAGCAACAAGAAGGCGCGAGGCAGATTGCCAGGAA
GGAATGGAAAGAAATCGGGAAGATCAAGGAGATCAAGGAGGGTTACCTGTCCTTGG
TGATACACGAGATTTCAAAAATGGTTATAAAATACAATGCCATTATCGCGATGGAG
GATTTGTCTTATGGATTTAAGAAGGGGAGGTTCAAAGTCGAACGACAAGTCTATCAG
AAGTTTGAAACAATGCTCATTAACAAGCTCAATTACCTTGTTTTCAAGGATATAAGC
ATCACTGAAAACGGCGGACTCCTTAAGGGATATCAGCTGACTTATATCCCCGACAAG
CTCAAGAACGTAGGGCACCAATGCGGATGCATCTTTTACGTGCCTGCAGCATATACT
TCAAAAATTGATCCGACTACTGGCTTTGTTAACATTTTCAAGTTCAAGGATCTGACG
GTAGACGCTAAGAGAGAATTCATAAAAAAGTTTGACAGCATCAGGTACGATAGTGA
AAAGAACCTTTTTTGTTTTACCTTTGACTACAATAATTTTATTACGCAAAATACAGTT
ATGAGCAAATCAAGTTGGAGCGTTTACACATATGGCGTTCGGATCAAGCGCAGATTC
GTCAATGGTCGCTTCTCAAATGAGAGCGATACAATCGATATAACGAAGGATATGGA
GAAGACGCTTGAGATGACAGATATCAACTGGCGGGACGGACATGACCTTAGACAAG
ACATAATCGATTACGAAATAGTACAGCATATCTTTGAGATTTTTAGGCTTACAGTTC
AGATGCGGAACTCTCTTTCCGAACTGGAGGACCGGGATTATGATCGGTTGATCTCCC
CAGTACTGAACGAAAATAATATCTTTTACGATAGCGCGAAGGCTGGTGATGCACTCC
CAAAAGACGCTGATGCGAACGGAGCTTATTGCATAGCCCTTAAAGGGCTTTACGAG
ATTAAACAAATAACAGAAAATTGGAAGGAAGATGGCAAATTTTCCCGCGACAAGTT
GAAGATTAGTAACAAAGACTGGTTCGACTTCATTCAGAATAAACGCTACCTCAAAC
GTCCGGCAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAG
CGGCGCAGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGT
AAGGTTATTCCGGGCTAA
SEQ ID NO: 64
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGTA
CCAATAACTTCCAGAACTTCATCGGTATTTCTAGCCTGCAAAAGACCCTGCGTAACG
CGCTGATTCCGACCGAGACTACCCAGCAATTCATCGTGAAAAACGGTATCATTAAGG
AAGATGAATTGCGCGGTGAGAATCGTCAGATTCTGAAAGATATCATGGATGACTAC
TATCGCGGTTTCATTAGCGAAACCCTGTCGAGCATCGATGATATCGATTGGACGAGC
CTCTTCGAGAAAATGGAAATTCAACTGAAAAATGGTGACAACAAAGATACCCTGAT
TAAAGAACAAACGGAATACCGCAAGGCAATCCATAAAAAGTTTGCGAATGACGACC
GTTTTAAGAATATGTTCTCGGCCAAGCTGATTTCCGACATCCTGCCAGAGTTCGTCAT
TCACAACAACAATTACAGCGCAAGCGAGAAAGAGGAAAAGACTCAGGTCATTAAGC
TGTTTAGCCGCTTTGCGACGTCCTTCAAAGACTACTTCAAGAATCGTGCGAATTGCTT
TAGCGCGGATGACATCTCTAGCTCTAGCTGTCACCGTATTGTTAACGACAATGCAGA
GATTTTCTTCAGCAACGCCCTGGTGTATCGCCGTATTGTCAAGTCTCTGAGCAACGA
CGACATTAACAAGATCAGCGGCGACATGAAAGACAGCCTGAAAGAAATGTCTCTGG
AAGAAATCTACAGCTACGAGAAATATGGTGAGTTTATCACCCAAGAGGGCATTAGC
TTCTACAATGATATCTGTGGTAAGGTTAATAGCTTTATGAATCTGTACTGCCAGAAG
AATAAAGAAAACAAGAACTTGTACAAGCTGCAAAAGCTGCATAAGCAAATTCTGTG
CATCGCCGATACTAGCTATGAAGTTCCGTACAAGTTCGAGTCTGATGAAGAGGTGTA
TCAGTCAGTCAACGGTTTTCTGGATAACATCAGCAGCAAGCACATCGTCGAGCGCCT
GCGCAAGATTGGTGACAACTACAATGGTTATAACCTGGACAAGATCTATATCGTGTC
GAAGTTTTACGAGAGCGTGTCCCAGAAAACGTACCGTGATTGGGAAACGATTAACA
CGGCCTTGGAAATTCACTATAACAATATCCTGCCGGGCAACGGCAAGAGCAAAGCT
GACAAAGTCAAAAAAGCTGTGAAAAACGATCTGCAAAAGTCCATCACCGAGATCAA
CGAACTGGTTAGCAACTATAAGCTGTGTAGCGACGACAACATTAAAGCTGAAACGT
ATATCCACGAAATCAGCCACATCCTGAATAACTTTGAGGCACAAGAACTGAAATAC
AATCCTGAGATCCATCTGGTAGAGAGCGAGCTGAAGGCAAGCGAGTTGAAAAACGT
TCTCGACGTTATCATGAATGCTTTCCACTGGTGTAGCGTGTTTATGACCGAAGAACT
GGTTGACAAAGATAACAATTTCTATGCAGAGCTGGAAGAAATCTATGATGAAATCT
ACCCGGTCATCAGCCTGTATAACCTGGTTCGTAACTACGTGACGCAGAAGCCGTACA
GCACCAAAAAGATCAAGCTGAACTTCGGTATTCCGACCTTGGCGGACGGTTGGAGC
AAATCCAAAGAATACTCCAATAATGCGATTATTCTGATGCGTGATAATCTGTACTAT
CTGGGTATCTTCAATGCGAAGAACAAGCCAGATAAAAAGATTATTGAAGGCAACAC
CAGCGAGAATAAAGGCGACTACAAGAAAATGATCTACAACTTATTGCCGGGTCCGA
ACAAGATGATCCCGAAAGTTTTTCTGAGCAGCAAGACCGGCGTTGAAACCTATAAG
CCGAGCGCGTACATTTTAGAGGGCTATAAACAAAACAAGCACATCAAGAGCAGCAA
AGATTTTGATATTACGTTCTGCCACGACCTGATCGACTATTTCAAGAATTGTATTGCG
ATTCACCCTGAGTGGAAGAACTTCGGTTTTGACTTTTCCGATACCTCCACCTATGAA
GATATTAGCGGTTTTTACCGTGAAGTCGAGTTGCAGGGTTATAAGATTGATTGGACT
TACATTTCCGAGAAAGACATCGACCTGTTGCAAGAGAAAGGTCAGCTGTACCTGTTT
CAGATCTATAACAAAGATTTCAGCAAAAAGTCGACGGGCAATGATAATCTGCACAC
CATGTATCTGAAAAACCTGTTTAGCGAAGAGAACCTGAAAGACATTGTTCTTAAGCT
GAATGGTGAGGCCGAGATCTTCTTCCGTAAAAGCTCCATTAAGAACCCGATTATCCA
CAAAAAGGGCTCTATTCTGGTTAACCGCACGTACGAAGCGGAAGAGAAAGATCAAT
TTGGTAACATCCAGATCGTGCGTAAGAATATCCCGGAGAACATTTACCAAGAACTGT
ATAAGTATTTCAATGACAAGAGCGATAAAGAATTGAGCGATGAAGCGGCAAAGCTG
AAAAACGTCGTTGGCCACCACGAAGCCGCGACGAATATCGTGAAAGATTATCGTTA
CACCTACGACAAGTACTTTCTGCACATGCCGATCACCATCAATTTCAAAGCGAATAA
AACGGGTTTTATCAATGACCGTATCCTGCAGTACATTGCGAAAGAAAAAGATTTACA
CGTGATTGGTATTGATCGCGGCGAGCGCAATCTGATTTACGTCAGCGTTATCGACAC
GTGCGGCAATATTGTGGAGCAGAAAAGCTTCAATATCGTCAATGGTTACGACTACCA
GATCAAACTGAAGCAACAAGAGGGCGCCCGCCAGATTGCGCGTAAAGAGTGGAAA
GAAATCGGTAAGATTAAAGAAATCAAGGAAGGCTACCTGTCCCTGGTGATCCATGA
AATCAGCAAAATGGTGATCAAGTACAACGCTATCATTGCGATGGAAGATCTGAGCT
ACGGTTTTAAAAAGGGTCGCTTCAAAGTTGAGCGTCAAGTGTATCAGAAATTTGAGA
CTATGCTGATTAACAAGTTGAACTATCTGGTTTTTAAAGACATCAGCATTACCGAGA
ATGGTGGCCTGCTGAAGGGTTATCAACTGACCTATATTCCTGACAAGTTGAAAAATG
TTGGTCATCAGTGTGGTTGCATTTTCTACGTACCGGCAGCGTACACGAGCAAGATTG
ACCCGACCACGGGTTTCGTTAACATTTTCAAGTTTAAAGATTTGACCGTGGACGCCA
AGCGTGAGTTCATTAAAAAGTTCGACAGCATCAGATACGACTCTGAGAAGAATCTG
TTCTGCTTTACGTTCGACTACAATAACTTCATTACCCAAAATACCGTTATGAGCAAA
AGCTCCTGGAGCGTGTACACGTACGGCGTCCGTATCAAGCGTCGTTTTGTGAATGGT
CGCTTTTCCAACGAATCTGACACCATTGACATTACCAAAGATATGGAAAAGACCCTT
GAGATGACCGACATTAATTGGCGTGATGGCCATGACTTGCGCCAAGACATTATCGAC
TACGAAATTGTTCAGCACATCTTTGAGATTTTTCGTCTGACGGTCCAGATGCGCAAC
TCGCTGAGCGAGTTGGAAGATCGTGACTATGACCGTCTGATTAGCCCGGTGCTGAAT
GAAAACAATATCTTCTATGATAGCGCAAAGGCCGGTGACGCGCTGCCGAAAGATGC
GGATGCTAACGGTGCATACTGCATTGCACTGAAGGGTCTGTACGAAATCAAACAGA
TCACCGAGAATTGGAAAGAGGATGGTAAGTTTAGCCGTGATAAGCTGAAGATTAGC
AATAAAGACTGGTTCGACTTTATTCAAAACAAGCGCTATCTGAAACGTCCGGCAGCG
ACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCA
GCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCG
GGCTAA
SEQ ID NO: 65
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGAA
CAAATAATTTTCAGAACTTTATTGGGATCAGTTCGCTTCAGAAAACGCTTCGTAATG
CTCTGATTCCCACAGAAACCACTCAGCAGTTTATCGTAAAGAATGGCATTATCAAGG
AGGATGAATTACGCGGCGAGAACCGCCAAATCTTAAAAGATATCATGGACGACTAC
TACCGCGGTTTCATTAGCGAAACTCTTAGTTCAATTGACGACATTGACTGGACGTCC
TTGTTCGAAAAGATGGAGATTCAATTAAAGAACGGTGATAACAAGGATACGTTGAT
TAAAGAACAGACGGAGTACCGTAAGGCTATCCACAAAAAATTTGCAAACGACGACC
GCTTTAAAAATATGTTTAGCGCAAAATTAATCTCCGACATCCTGCCTGAATTCGTCA
TCCATAACAATAACTATAGCGCCTCGGAAAAAGAAGAAAAAACGCAGGTTATTAAA
CTTTTCTCGCGCTTTGCAACAAGCTTTAAGGATTACTTCAAAAATCGCGCCAATTGTT
TTTCAGCCGACGACATTAGCTCCAGTTCCTGCCACCGTATTGTGAATGACAACGCTG
AGATTTTTTTTTCCAATGCGCTGGTTTATCGTCGTATTGTTAAGAGCCTTAGTAACGA
CGACATTAATAAAATTAGCGGTGATATGAAGGATAGCTTGAAAGAAATGAGTCTGG
AAGAGATCTATAGTTACGAGAAGTACGGCGAATTTATTACCCAGGAGGGCATTTCAT
TTTACAATGATATCTGTGGAAAAGTCAACTCCTTTATGAACTTGTATTGCCAAAAGA
ATAAAGAAAACAAAAACCTGTACAAACTGCAAAAGTTACACAAGCAGATTTTGTGT
ATCGCAGACACGTCATACGAAGTACCGTACAAGTTTGAGTCCGATGAAGAAGTGTA
CCAAAGCGTTAATGGCTTTTTGGATAACATTTCGAGCAAACATATCGTAGAGCGTTT
GCGTAAGATTGGTGATAATTACAACGGTTACAATTTAGACAAAATCTATATCGTCTC
TAAGTTTTACGAAAGTGTTTCTCAGAAAACTTACCGCGATTGGGAGACGATCAACAC
TGCGCTGGAGATTCATTACAATAATATCCTTCCAGGTAACGGTAAAAGCAAAGCTGA
TAAGGTGAAAAAGGCGGTTAAAAATGACCTTCAAAAGTCTATCACAGAAATCAACG
AATTGGTCAGCAATTATAAGCTTTGCAGTGACGATAACATTAAGGCCGAGACTTACA
TCCATGAGATCTCTCACATTCTTAATAATTTTGAAGCGCAAGAGCTGAAATACAATC
CTGAAATCCATCTGGTCGAAAGTGAATTAAAAGCCTCCGAATTAAAAAATGTCTTGG
ACGTGATCATGAATGCGTTCCATTGGTGCTCAGTTTTTATGACGGAAGAGTTGGTGG
ACAAAGACAACAATTTTTACGCCGAGCTTGAGGAAATTTACGACGAAATTTACCCCG
TTATTTCGTTATACAACCTTGTGCGTAATTACGTTACACAAAAGCCCTATTCGACAA
AGAAAATCAAGTTAAATTTCGGGATTCCCACATTAGCTGATGGATGGTCCAAATCCA
AAGAATACTCGAATAACGCTATCATCCTTATGCGTGATAATTTGTACTACTTAGGCA
TCTTCAATGCGAAGAACAAACCTGACAAGAAAATTATCGAAGGAAACACTTCGGAG
AACAAAGGTGATTATAAAAAGATGATCTACAACTTGCTTCCCGGGCCAAACAAAAT
GATTCCCAAGGTATTTTTGAGTTCTAAAACCGGTGTCGAAACTTACAAACCAAGTGC
TTATATTTTGGAAGGATACAAACAGAACAAACATATCAAGTCTTCGAAAGACTTCGA
TATTACGTTCTGCCACGATCTGATCGATTACTTCAAGAACTGTATTGCTATTCACCCC
GAGTGGAAGAACTTTGGATTTGATTTCTCCGACACGTCCACTTATGAAGATATCTCT
GGCTTCTATCGCGAGGTTGAATTACAAGGGTATAAGATTGACTGGACTTATATTTCG
GAGAAGGATATCGATCTTTTGCAAGAAAAAGGGCAACTTTATTTATTTCAGATCTAT
AACAAGGACTTTTCAAAAAAGAGCACTGGAAATGACAATCTGCATACCATGTACCT
TAAGAACCTGTTCTCGGAAGAGAACCTGAAGGACATTGTACTTAAACTGAATGGAG
AGGCAGAGATCTTCTTTCGCAAATCAAGCATTAAGAACCCAATTATTCACAAAAAG
GGGAGTATCTTAGTAAATCGCACATATGAGGCTGAGGAAAAAGATCAGTTTGGTAA
CATTCAGATCGTGCGTAAGAACATTCCTGAAAATATCTATCAGGAACTTTATAAGTA
TTTCAACGATAAAAGTGATAAAGAGCTGAGTGACGAAGCGGCTAAACTTAAGAATG
TTGTGGGACACCATGAGGCAGCAACCAATATTGTGAAGGATTATCGCTATACGTACG
ACAAATACTTTTTACACATGCCCATCACTATTAATTTTAAAGCTAATAAGACTGGCTT
CATTAACGATCGCATCCTGCAGTACATTGCTAAGGAAAAGGATCTTCACGTTATCGG
TATCGATCGCGGGGAGCGTAATCTTATCTACGTCTCTGTCATTGACACGTGTGGCAA
TATTGTGGAGCAAAAGTCCTTCAATATTGTTAACGGCTATGACTATCAGATTAAATT
GAAACAGCAGGAAGGTGCGCGTCAGATTGCCCGCAAGGAATGGAAGGAAATTGGC
AAGATCAAAGAAATTAAGGAGGGCTACTTAAGCTTAGTAATTCACGAAATTAGTAA
AATGGTTATCAAATACAACGCCATCATCGCGATGGAGGATCTTTCGTACGGGTTTAA
GAAAGGTCGTTTTAAAGTGGAGCGTCAGGTGTACCAGAAATTTGAAACTATGCTTAT
TAACAAACTTAACTACCTGGTTTTCAAGGATATCAGTATTACTGAAAACGGGGGGCT
GTTAAAAGGGTATCAATTAACTTACATTCCAGACAAATTAAAGAACGTTGGACATCA
GTGTGGCTGCATTTTTTATGTACCAGCTGCATACACTTCAAAGATCGATCCTACGACT
GGGTTCGTGAACATTTTTAAGTTTAAAGACTTGACGGTAGATGCCAAGCGCGAATTC
ATCAAGAAATTCGACAGCATTCGCTACGACTCTGAGAAAAATCTTTTCTGTTTCACA
TTCGATTATAACAATTTCATTACGCAGAACACAGTAATGTCCAAGTCTTCTTGGAGT
GTTTATACATATGGTGTCCGCATTAAGCGCCGTTTCGTCAACGGCCGCTTCAGTAAT
GAGAGCGATACTATTGACATCACAAAAGACATGGAAAAAACACTGGAAATGACCGA
CATCAATTGGCGTGACGGCCATGACTTACGTCAGGATATCATTGATTATGAGATCGT
TCAACACATCTTCGAAATCTTTCGCTTGACTGTTCAAATGCGCAATTCCTTGTCGGAA
TTGGAGGACCGTGATTATGACCGCTTAATTTCCCCCGTCTTAAATGAAAACAATATT
TTTTATGACTCTGCAAAAGCTGGAGATGCTCTGCCGAAAGACGCCGATGCAAATGG
GGCATATTGCATTGCTTTAAAGGGGCTTTACGAGATCAAGCAAATCACCGAAAACTG
GAAAGAGGATGGAAAGTTTTCGCGTGATAAACTGAAGATCTCTAACAAAGACTGGT
TCGACTTTATCCAGAACAAGCGTTATTTGAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 66
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGCA
CCAATAACTTCCAAAACTTCATCGGGATCTCTAGCCTTCAGAAGACGCTTCGCAATG
CTCTTATCCCAACTGAGACCACTCAACAATTTATTGTGAAGAATGGAATTATTAAAG
AGGACGAACTGCGTGGCGAGAATCGTCAGATCTTAAAGGACATTATGGATGATTAT
TACCGTGGATTCATCTCCGAAACATTATCGTCGATCGATGATATCGATTGGACTTCTC
TGTTCGAGAAAATGGAAATTCAATTGAAAAACGGAGATAATAAAGATACGCTTATC
AAAGAACAGACGGAATATCGTAAAGCGATTCATAAGAAATTCGCAAATGACGATCG
TTTCAAAAATATGTTCAGTGCCAAGCTTATTTCGGACATTTTACCTGAATTTGTAATT
CATAATAATAACTACTCAGCAAGTGAGAAGGAGGAGAAAACCCAAGTTATTAAACT
GTTCTCTCGTTTCGCAACGTCCTTTAAAGATTACTTTAAAAACCGCGCGAATTGCTTT
AGCGCTGACGACATTTCCAGCTCATCCTGTCATCGCATCGTAAACGACAATGCGGAA
ATCTTCTTCAGCAACGCCCTGGTTTACCGCCGCATCGTCAAAAGCTTATCGAATGAC
GACATCAATAAGATCTCAGGAGATATGAAGGACTCGCTTAAGGAGATGTCTCTGGA
GGAAATTTATAGTTACGAAAAGTATGGAGAGTTCATTACCCAGGAGGGAATCTCGTT
CTACAATGACATTTGCGGGAAGGTGAACTCCTTCATGAACTTATACTGCCAGAAAAA
CAAAGAGAACAAAAATCTGTATAAATTGCAGAAATTACATAAACAGATTCTTTGTAT
TGCTGACACTTCCTACGAAGTACCCTATAAATTCGAGTCAGATGAAGAAGTATACCA
GTCCGTGAACGGATTTCTGGACAATATCTCCTCAAAACACATCGTGGAACGCTTACG
TAAAATTGGCGATAATTATAATGGTTACAATCTTGACAAAATTTATATCGTATCTAA
ATTTTACGAGAGTGTGAGCCAAAAGACCTACCGCGACTGGGAGACCATCAACACAG
CTTTAGAAATTCACTATAATAATATCTTACCCGGCAATGGTAAGAGCAAGGCTGACA
AGGTAAAAAAGGCCGTCAAGAATGATTTGCAGAAATCTATTACAGAAATTAATGAG
TTAGTCTCCAACTATAAGCTTTGTTCCGACGATAACATCAAAGCTGAGACATATATT
CATGAGATTAGTCACATTCTTAACAACTTCGAGGCCCAGGAACTTAAGTACAATCCT
GAAATTCATCTTGTCGAGTCTGAGCTGAAAGCTAGTGAATTGAAAAATGTTTTAGAC
GTTATTATGAACGCATTCCACTGGTGCTCTGTGTTTATGACAGAAGAACTGGTCGAC
AAGGACAATAACTTCTATGCCGAACTTGAGGAAATCTACGATGAAATTTACCCTGTA
ATCTCCTTGTATAATCTTGTACGTAATTACGTCACTCAAAAACCTTACAGCACGAAA
AAAATTAAATTGAACTTCGGGATTCCTACACTTGCCGACGGGTGGTCTAAATCCAAG
GAATATAGCAACAATGCCATTATTTTAATGCGCGACAATCTTTACTATTTAGGAATT
TTTAACGCTAAGAACAAGCCCGATAAAAAGATTATTGAAGGAAACACGTCTGAAAA
TAAGGGCGACTACAAAAAGATGATTTATAACCTTTTGCCCGGTCCAAACAAAATGAT
CCCAAAGGTATTCCTGTCATCCAAAACAGGGGTTGAGACATATAAGCCCAGCGCAT
ATATTCTGGAAGGATACAAACAGAATAAACATATCAAAAGCAGCAAAGATTTTGAC
ATTACTTTTTGCCACGATTTAATCGACTACTTCAAAAACTGTATCGCTATCCACCCTG
AATGGAAGAATTTCGGATTTGATTTCTCAGATACAAGTACGTATGAGGATATCAGCG
GTTTCTATCGCGAAGTTGAACTTCAAGGGTATAAAATTGACTGGACCTACATTAGTG
AGAAGGACATCGACCTGTTACAGGAAAAAGGCCAATTGTACTTGTTTCAGATCTACA
ATAAGGATTTCTCAAAAAAATCGACCGGCAATGATAACTTGCACACCATGTACCTGA
AGAACCTTTTTTCGGAGGAAAACCTTAAAGACATTGTCCTGAAGTTGAATGGAGAA
GCGGAGATTTTCTTTCGTAAGTCTTCCATTAAAAATCCAATTATTCATAAGAAGGGC
AGCATCCTTGTGAACCGTACGTACGAGGCGGAAGAGAAGGACCAATTCGGTAACAT
TCAAATCGTCCGCAAGAACATCCCTGAAAATATTTATCAGGAGCTTTACAAGTATTT
CAATGATAAGTCCGACAAGGAATTATCAGATGAGGCTGCGAAGTTGAAAAATGTTG
TTGGTCATCACGAGGCGGCGACGAATATTGTAAAGGATTATCGCTACACTTATGACA
AGTACTTTCTGCACATGCCGATCACCATTAATTTCAAGGCGAACAAAACAGGATTTA
TTAATGACCGCATCTTACAATACATTGCCAAAGAAAAGGACTTACACGTTATTGGCA
TTGATCGTGGAGAACGCAACTTAATCTACGTAAGCGTTATTGACACTTGCGGGAATA
TCGTAGAACAAAAGAGCTTCAACATCGTGAATGGTTACGATTACCAGATCAAGCTTA
AGCAGCAGGAGGGAGCGCGCCAGATCGCGCGCAAGGAATGGAAGGAGATTGGTAA
GATCAAGGAAATCAAGGAAGGTTATCTGTCCTTGGTAATCCACGAAATTTCGAAAAT
GGTTATCAAATACAATGCTATTATTGCAATGGAGGACTTGTCCTACGGCTTTAAAAA
AGGACGCTTTAAGGTGGAGCGCCAGGTTTATCAAAAGTTTGAAACAATGCTGATTA
ACAAGCTGAACTATTTGGTCTTTAAAGATATCTCCATCACCGAAAATGGTGGGCTTT
TGAAAGGCTATCAACTTACATATATCCCTGATAAGCTTAAGAATGTGGGTCATCAGT
GCGGGTGCATTTTTTATGTTCCTGCAGCCTACACGTCCAAAATCGATCCTACAACTG
GATTTGTTAATATCTTCAAATTTAAGGATCTTACCGTCGACGCGAAGCGCGAATTTA
TCAAGAAATTCGATAGTATTCGTTATGATTCCGAAAAAAACCTTTTCTGTTTCACCTT
TGATTATAATAACTTTATCACGCAAAATACTGTCATGAGCAAATCGAGTTGGTCTGT
GTACACTTACGGAGTACGCATCAAGCGTCGTTTTGTTAATGGGCGCTTCAGTAACGA
GTCAGACACGATTGATATCACAAAAGATATGGAGAAAACGCTGGAGATGACAGACA
TCAATTGGCGCGATGGTCATGACTTACGTCAAGACATTATCGATTATGAAATTGTCC
AGCATATCTTTGAGATCTTTCGTTTGACTGTTCAGATGCGCAACAGCCTGTCAGAATT
GGAGGATCGTGACTATGATCGCCTTATTTCTCCCGTCTTAAATGAGAACAATATCTT
CTACGACTCAGCCAAGGCTGGAGATGCACTGCCAAAAGACGCCGACGCAAATGGGG
CCTACTGTATTGCATTGAAGGGGTTGTACGAGATCAAACAGATTACAGAAAATTGG
AAGGAGGACGGTAAGTTCTCTCGTGATAAGCTGAAGATTTCTAACAAAGACTGGTTC
GATTTCATTCAGAACAAACGTTACCTGAAACGTCCGGCAGCGACCAAAAAAGCCGG
CCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAAA
CGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 67
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGTA
CCAATAACTTTCAGAATTTCATTGGAATCAGCAGCTTACAGAAAACCCTGCGCAATG
CACTTATCCCCACTGAGACAACCCAGCAGTTCATTGTAAAGAACGGGATTATTAAAG
AAGATGAGCTTCGCGGGGAGAATCGTCAGATCTTAAAGGATATTATGGACGATTAC
TACCGTGGCTTCATTTCGGAGACGCTGTCGTCGATCGACGACATCGACTGGACATCC
TTGTTTGAAAAGATGGAAATCCAACTGAAGAATGGCGATAACAAGGACACGTTAAT
CAAAGAGCAGACGGAATACCGTAAAGCTATCCACAAAAAGTTCGCTAATGACGACC
GCTTTAAGAACATGTTCTCAGCAAAACTTATTAGCGATATTTTACCTGAATTTGTCAT
CCACAATAACAATTACTCCGCGAGTGAAAAAGAGGAGAAAACCCAGGTGATTAAGC
TGTTTTCCCGTTTTGCAACCAGTTTCAAGGACTATTTTAAGAATCGTGCTAATTGTTT
CTCTGCAGACGACATTTCCTCGTCGTCCTGCCATCGCATTGTTAATGATAATGCTGAA
ATCTTTTTTTCAAACGCACTTGTGTATCGTCGCATTGTCAAAAGCTTAAGTAATGACG
ATATCAATAAGATCTCAGGAGACATGAAGGACTCCCTGAAAGAAATGTCATTGGAA
GAAATTTACTCTTATGAAAAGTATGGAGAATTTATTACGCAGGAGGGTATCAGCTTC
TATAACGACATTTGTGGTAAAGTGAACAGCTTTATGAATCTTTATTGTCAAAAGAAT
AAAGAGAACAAAAATCTGTACAAGCTGCAGAAATTGCATAAACAAATTCTGTGCAT
TGCAGATACTTCGTATGAGGTTCCTTACAAATTCGAGTCGGATGAGGAGGTGTATCA
AAGCGTAAACGGATTTTTGGATAACATTAGTAGTAAGCATATTGTGGAACGCCTTCG
CAAGATTGGTGACAACTATAACGGATACAACTTAGACAAGATCTATATTGTCTCGAA
GTTTTACGAAAGTGTTTCCCAAAAGACTTATCGCGACTGGGAGACAATCAACACTGC
GCTGGAAATTCACTATAACAATATCTTGCCGGGGAACGGAAAAAGTAAGGCAGATA
AGGTGAAGAAAGCAGTCAAAAATGATCTGCAAAAAAGCATTACTGAAATTAACGAA
CTTGTGTCAAATTACAAATTGTGTTCGGATGACAATATTAAAGCGGAAACGTATATC
CACGAGATCTCGCACATTCTTAATAATTTCGAGGCGCAGGAATTAAAGTATAATCCT
GAGATCCATTTGGTGGAATCAGAACTTAAAGCTAGTGAACTGAAAAATGTCCTGGA
CGTTATTATGAATGCATTTCACTGGTGTTCTGTCTTTATGACAGAAGAACTTGTCGAC
AAAGACAACAACTTTTATGCGGAATTAGAAGAGATTTACGACGAAATTTATCCCGTT
ATTTCGTTATATAATTTAGTTCGTAATTACGTGACTCAGAAACCCTACAGCACAAAA
AAGATTAAATTAAACTTTGGGATTCCGACTCTTGCTGATGGATGGAGCAAGTCCAAG
GAGTACTCTAATAACGCCATTATCTTGATGCGTGACAACCTGTACTACCTGGGCATT
TTTAACGCTAAAAACAAACCCGACAAAAAGATCATTGAAGGGAACACCTCGGAAAA
TAAGGGGGACTATAAAAAAATGATCTACAATCTGTTGCCAGGCCCAAATAAGATGA
TCCCAAAGGTTTTTTTATCTTCCAAAACTGGCGTAGAAACTTACAAGCCGAGCGCAT
ACATCCTTGAAGGATATAAACAAAACAAACATATCAAAAGTTCAAAGGACTTCGAT
ATTACGTTCTGCCATGATTTAATCGATTATTTCAAGAATTGCATCGCGATTCACCCAG
AGTGGAAAAACTTTGGGTTTGATTTTTCAGACACCAGCACTTACGAGGATATTAGTG
GATTCTATCGTGAGGTTGAACTGCAGGGCTATAAAATTGACTGGACCTATATTTCTG
AAAAAGATATTGATCTGCTTCAGGAGAAAGGCCAATTGTACTTATTTCAAATCTATA
ACAAGGATTTCTCCAAGAAGTCCACGGGTAATGACAACTTACACACAATGTATCTGA
AGAATCTGTTTAGTGAGGAGAACTTGAAGGACATTGTGCTGAAGCTTAATGGCGAG
GCCGAAATCTTTTTTCGTAAGTCCTCCATTAAAAACCCTATTATCCATAAGAAAGGG
AGTATTCTTGTCAACCGCACGTATGAGGCCGAAGAAAAGGACCAATTCGGAAACAT
CCAAATTGTCCGTAAAAATATTCCTGAGAACATTTACCAGGAGCTTTACAAGTATTT
CAACGACAAGAGTGATAAAGAACTTTCAGATGAGGCGGCGAAACTGAAGAATGTAG
TGGGGCACCACGAAGCTGCCACGAATATTGTAAAGGATTACCGTTACACCTACGAC
AAGTACTTTTTGCATATGCCCATCACAATTAATTTTAAGGCCAATAAAACTGGTTTTA
TCAACGATCGTATCTTACAGTACATTGCTAAGGAAAAAGATCTGCACGTTATCGGTA
TCGATCGCGGGGAACGCAATCTGATTTATGTTAGTGTGATTGACACGTGCGGAAATA
TTGTTGAGCAGAAGAGCTTTAATATCGTAAATGGATATGACTATCAAATTAAACTGA
AGCAACAGGAAGGGGCCCGCCAGATTGCCCGCAAGGAGTGGAAAGAAATTGGAAA
GATCAAGGAGATTAAAGAAGGGTACCTTTCCCTTGTTATCCACGAAATCTCGAAAAT
GGTGATCAAGTACAATGCCATTATTGCTATGGAGGATCTGTCATATGGGTTTAAGAA
AGGCCGCTTTAAGGTGGAACGTCAGGTTTACCAGAAGTTTGAGACCATGCTTATCAA
TAAGCTGAATTATCTTGTCTTCAAAGACATCTCAATCACAGAGAACGGCGGGCTGTT
AAAAGGATATCAGCTGACCTATATCCCCGACAAACTGAAAAATGTCGGGCACCAAT
GCGGCTGTATTTTCTACGTGCCCGCTGCATACACATCTAAAATTGACCCAACGACTG
GATTCGTAAATATTTTTAAGTTTAAGGATCTTACGGTAGATGCAAAGCGCGAATTTA
TCAAGAAATTTGATAGTATCCGTTACGACAGCGAGAAAAACTTATTTTGTTTTACGT
TCGATTATAACAACTTCATCACGCAAAATACCGTCATGTCAAAATCTTCCTGGTCAG
TCTATACGTATGGCGTCCGTATCAAGCGCCGCTTCGTCAACGGGCGTTTTTCAAACG
AGTCAGATACCATCGATATCACCAAAGATATGGAAAAAACATTGGAGATGACGGAC
ATCAATTGGCGCGATGGTCATGACTTACGCCAGGACATTATTGACTACGAAATCGTA
CAACATATTTTTGAGATTTTCCGTCTGACCGTGCAAATGCGCAACTCATTATCCGAA
CTTGAGGATCGTGATTACGACCGCTTGATCAGTCCTGTTCTGAACGAGAATAATATT
TTTTACGACAGTGCCAAGGCGGGAGACGCACTGCCCAAGGACGCTGACGCTAACGG
AGCTTATTGTATTGCGTTGAAGGGACTTTACGAAATCAAGCAAATCACTGAAAACTG
GAAGGAGGATGGTAAATTCTCACGCGACAAGTTGAAAATTTCGAACAAGGACTGGT
TCGATTTCATCCAAAACAAGCGTTATTTAAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 68
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGGA
CTAATAACTTCCAGAACTTCATCGGTATTTCATCATTACAAAAAACGCTTCGTAACG
CCTTGATCCCAACAGAAACGACCCAACAATTTATTGTAAAAAACGGCATCATCAAA
GAAGACGAACTGCGTGGCGAAAATCGCCAAATTTTGAAGGACATTATGGATGACTA
TTATCGTGGGTTTATCTCGGAGACATTATCCTCCATCGACGACATTGATTGGACGAG
TCTTTTTGAGAAAATGGAGATCCAGCTTAAAAATGGTGATAACAAGGATACATTGAT
CAAGGAGCAAACCGAGTACCGCAAGGCCATCCATAAGAAGTTCGCAAATGACGACC
GCTTCAAAAATATGTTTAGTGCCAAATTGATCTCGGATATCCTTCCTGAGTTCGTAAT
TCACAACAATAATTATAGCGCATCCGAAAAGGAGGAAAAGACTCAAGTCATTAAGC
TTTTCAGTCGCTTTGCTACCTCGTTTAAGGACTATTTCAAGAACCGCGCGAACTGCTT
CTCAGCGGATGACATTTCTTCCTCGTCGTGTCACCGCATCGTGAATGATAATGCGGA
GATCTTCTTTAGTAATGCCTTGGTATACCGCCGCATTGTTAAATCCCTGTCTAACGAC
GATATCAATAAGATCTCAGGAGATATGAAGGATAGCCTTAAAGAAATGTCTCTGGA
AGAAATTTACTCCTATGAAAAGTACGGTGAGTTTATCACCCAAGAGGGGATTAGCTT
TTATAACGATATCTGCGGGAAGGTGAATTCGTTTATGAACCTTTATTGTCAAAAGAA
TAAGGAGAATAAGAACTTATATAAGCTTCAGAAACTGCATAAACAAATCTTATGCA
TTGCCGATACTAGCTATGAAGTTCCGTATAAATTCGAGAGCGATGAAGAAGTTTATC
AGAGCGTCAATGGGTTCTTGGATAACATTTCATCAAAACACATCGTGGAACGTCTGC
GTAAGATTGGGGATAACTACAACGGATATAATCTTGACAAAATTTATATTGTATCTA
AATTCTATGAGTCGGTGAGTCAAAAGACCTACCGTGATTGGGAAACAATCAATACC
GCGTTAGAAATCCACTATAACAACATTCTGCCAGGGAATGGTAAAAGTAAAGCGGA
CAAAGTCAAGAAGGCTGTGAAGAACGATCTGCAAAAGAGTATTACAGAGATTAACG
AATTAGTCTCCAATTATAAGTTATGCTCGGACGATAACATTAAGGCGGAGACGTATA
TTCATGAGATTTCGCATATTCTTAACAACTTCGAGGCACAAGAGCTTAAGTATAACC
CAGAGATTCACCTTGTCGAATCGGAGCTGAAGGCATCGGAATTAAAAAATGTCTTA
GATGTAATCATGAACGCGTTCCATTGGTGCAGTGTTTTCATGACTGAGGAGTTAGTT
GACAAGGACAATAACTTCTACGCAGAATTAGAAGAGATCTATGATGAGATTTATCC
AGTGATTTCGCTGTATAATCTGGTACGTAATTACGTCACTCAAAAGCCCTACTCAAC
AAAAAAAATTAAGCTGAACTTCGGAATTCCGACTCTGGCCGACGGGTGGTCCAAGT
CAAAGGAGTATTCTAATAATGCTATCATCCTGATGCGCGATAACTTATACTATTTGG
GAATTTTCAATGCCAAAAATAAACCAGATAAAAAGATTATCGAAGGTAATACAAGC
GAGAATAAGGGTGACTATAAGAAAATGATTTACAATCTTCTTCCAGGCCCTAACAA
GATGATTCCCAAAGTTTTTTTGTCCAGTAAAACAGGGGTCGAAACTTACAAGCCCAG
TGCCTATATCCTTGAAGGGTACAAGCAGAATAAGCACATCAAATCCTCGAAAGACTT
TGATATTACATTTTGTCATGACTTAATCGATTATTTTAAGAACTGTATCGCAATCCAT
CCAGAATGGAAGAACTTCGGGTTTGATTTCTCTGATACTTCCACGTATGAGGATATT
TCCGGGTTCTACCGCGAAGTAGAGCTTCAGGGCTATAAAATTGACTGGACATATATT
TCAGAAAAAGACATCGATCTGTTACAAGAAAAAGGACAGTTGTATCTGTTTCAAATC
TATAATAAGGATTTCTCCAAAAAGTCAACTGGAAATGATAACTTACATACAATGTAT
CTGAAAAATCTTTTTAGTGAAGAGAATTTGAAGGATATCGTGCTGAAGTTAAATGGC
GAAGCAGAGATCTTCTTCCGCAAGTCCTCGATCAAGAATCCTATCATCCACAAGAAA
GGTAGTATTCTGGTTAACCGCACGTACGAGGCCGAGGAAAAAGACCAGTTCGGTAA
TATCCAGATTGTACGTAAGAATATTCCTGAAAATATTTACCAGGAATTATACAAGTA
TTTTAACGACAAATCGGATAAGGAGCTTTCAGATGAGGCCGCAAAGTTGAAGAACG
TCGTAGGACACCATGAGGCCGCTACGAATATCGTCAAGGACTACCGCTATACGTATG
ACAAGTACTTCCTGCACATGCCTATTACTATCAATTTCAAAGCTAATAAAACAGGAT
TCATCAATGATCGTATCCTTCAGTACATTGCCAAAGAAAAAGATCTGCACGTAATCG
GAATCGACCGTGGCGAACGTAATCTGATTTACGTATCAGTTATCGACACATGTGGTA
ACATCGTGGAGCAGAAATCTTTTAACATTGTTAACGGCTATGATTATCAGATTAAGC
TTAAACAGCAGGAGGGGGCACGCCAAATCGCTCGTAAAGAATGGAAGGAGATTGG
AAAGATTAAAGAGATTAAAGAGGGGTACCTTTCGCTGGTTATTCACGAAATTTCCAA
GATGGTGATTAAGTACAATGCAATCATCGCGATGGAAGATCTTAGTTACGGATTCAA
AAAGGGACGCTTCAAAGTTGAGCGTCAGGTCTACCAGAAATTTGAAACGATGCTGA
TTAACAAATTGAATTACTTGGTATTCAAAGATATCTCAATTACTGAAAATGGTGGCT
TATTAAAGGGTTACCAGCTTACCTATATCCCGGATAAGCTGAAGAACGTGGGCCATC
AATGCGGCTGCATCTTTTACGTCCCTGCCGCATATACCTCTAAAATTGACCCCACCA
CCGGATTCGTAAATATTTTTAAATTCAAGGACCTGACGGTGGACGCCAAGCGCGAAT
TCATCAAAAAATTCGACTCAATCCGCTATGATTCCGAAAAAAATCTTTTCTGCTTTAC
GTTCGATTATAATAACTTCATTACCCAAAACACGGTGATGTCAAAATCGTCCTGGAG
CGTGTATACTTATGGAGTGCGTATCAAGCGCCGCTTTGTTAATGGGCGCTTCAGTAA
CGAAAGCGATACCATCGACATTACCAAAGACATGGAGAAGACGCTTGAAATGACGG
ATATCAATTGGCGTGACGGACACGATCTTCGTCAGGATATCATCGACTACGAGATTG
TGCAACATATCTTTGAGATTTTCCGTTTAACTGTTCAAATGCGTAACTCCTTGTCCGA
ATTGGAAGACCGTGATTACGACCGCTTGATTTCACCAGTGCTTAACGAGAATAACAT
CTTCTACGACTCCGCCAAAGCAGGCGATGCCCTGCCAAAGGACGCTGATGCAAATG
GTGCATACTGTATCGCGTTGAAGGGCTTATACGAGATTAAGCAAATCACCGAAAATT
GGAAAGAGGATGGAAAGTTCAGTCGCGATAAGCTGAAGATCTCTAATAAAGATTGG
TTTGACTTTATCCAGAACAAACGTTATTTAAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 69
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGTA
CCAATAATTTCCAAAATTTCATCGGAATCTCATCCTTGCAAAAAACCTTGCGCAATG
CTTTGATCCCCACCGAAACCACGCAGCAGTTCATCGTGAAAAACGGCATTATCAAAG
AGGATGAGTTGCGCGGGGAAAACCGTCAAATTCTTAAGGATATCATGGACGATTAC
TACCGTGGGTTTATCAGTGAGACCCTGTCAAGCATTGACGACATTGACTGGACCAGC
TTATTTGAGAAGATGGAGATTCAATTAAAGAACGGGGACAATAAGGACACGCTTAT
CAAAGAGCAGACAGAATACCGTAAAGCGATTCATAAGAAATTTGCAAATGACGATC
GCTTCAAGAACATGTTTTCAGCAAAATTAATCAGCGACATCCTTCCCGAATTTGTGA
TTCATAATAACAACTATTCGGCTAGCGAAAAAGAGGAGAAAACTCAGGTTATTAAG
CTTTTCTCGCGTTTTGCCACTTCGTTCAAAGACTATTTTAAGAATCGCGCAAACTGCT
TTTCGGCTGATGATATTTCCAGTTCTAGCTGCCATCGTATCGTTAACGATAATGCTGA
GATTTTCTTCTCTAATGCCCTGGTGTATCGTCGTATCGTTAAATCTTTGAGCAACGAC
GATATTAATAAGATTTCAGGCGACATGAAGGATTCTTTAAAGGAGATGTCTTTAGAA
GAGATTTATTCCTATGAGAAATATGGCGAGTTTATCACCCAAGAAGGAATTTCGTTC
TACAACGACATCTGTGGCAAAGTGAACAGCTTCATGAATTTATACTGCCAAAAGAAT
AAGGAGAATAAAAATTTATATAAACTGCAGAAACTGCATAAGCAAATTCTTTGCATT
GCAGACACCTCTTATGAAGTTCCTTATAAGTTTGAATCGGACGAGGAGGTATATCAG
AGTGTGAACGGGTTCCTGGACAATATTTCATCCAAGCATATTGTTGAACGTTTACGC
AAAATTGGAGACAATTACAATGGGTATAACCTTGACAAAATTTACATCGTGTCGAA
GTTTTACGAATCGGTAAGCCAGAAGACCTATCGTGACTGGGAAACTATCAATACCGC
CTTAGAAATTCATTACAACAATATTCTTCCTGGTAACGGCAAAAGCAAAGCCGATAA
GGTAAAGAAGGCTGTCAAGAACGACCTGCAAAAGTCTATCACAGAGATCAACGAGT
TAGTCTCTAACTACAAATTATGTTCCGACGACAATATTAAAGCCGAAACCTACATCC
ATGAGATCTCACACATTCTTAACAATTTTGAGGCCCAGGAGCTGAAATATAACCCAG
AAATTCACCTTGTAGAGAGCGAATTAAAAGCCTCCGAGCTGAAGAACGTTTTGGAT
GTAATCATGAACGCATTTCATTGGTGCAGCGTATTTATGACAGAGGAGTTGGTCGAC
AAGGACAATAACTTTTACGCCGAGCTTGAAGAAATCTACGATGAAATTTACCCGGTA
ATTAGTTTATATAATTTAGTTCGCAACTACGTAACTCAGAAACCCTACAGTACCAAG
AAGATTAAATTGAACTTTGGGATCCCGACACTTGCTGACGGTTGGAGTAAATCAAAA
GAATACTCCAATAATGCAATTATCCTGATGCGCGACAATCTTTACTACTTGGGGATC
TTTAACGCAAAGAACAAACCAGATAAGAAAATCATCGAGGGCAACACCAGCGAGA
ATAAAGGCGATTACAAGAAAATGATCTATAATCTTTTGCCGGGACCGAACAAAATG
ATCCCAAAGGTTTTCCTGTCGTCGAAAACGGGAGTCGAGACATATAAACCATCTGCG
TACATCTTGGAAGGTTACAAACAGAATAAGCATATTAAGTCTAGTAAAGACTTCGAC
ATCACCTTTTGTCATGACCTGATTGATTATTTCAAGAACTGTATTGCTATCCATCCAG
AATGGAAAAACTTCGGATTTGACTTCTCCGATACTAGCACCTACGAAGACATTTCGG
GTTTTTATCGCGAAGTAGAGCTTCAAGGGTACAAAATTGATTGGACATATATTAGCG
AGAAAGACATTGATTTGCTTCAAGAGAAGGGACAGTTATATTTATTCCAGATCTACA
ACAAAGACTTCTCGAAGAAATCCACCGGTAATGATAATCTTCACACTATGTACCTGA
AGAATTTATTTTCAGAGGAAAATCTGAAGGACATTGTACTTAAACTTAATGGAGAAG
CCGAAATCTTCTTCCGCAAGAGTTCCATTAAAAATCCGATTATTCATAAAAAGGGAA
GTATCCTTGTGAACCGCACGTATGAGGCCGAAGAGAAGGATCAGTTTGGGAATATT
CAAATTGTCCGCAAAAACATCCCCGAGAACATCTACCAGGAACTGTATAAATACTTT
AATGATAAATCTGATAAAGAGTTATCAGACGAGGCTGCCAAACTGAAAAACGTAGT
CGGTCATCATGAGGCAGCGACCAATATTGTAAAGGACTACCGTTACACCTACGACA
AGTATTTCCTTCACATGCCGATCACGATTAATTTTAAGGCTAACAAGACCGGCTTTA
TCAATGACCGCATCTTGCAGTACATCGCGAAAGAGAAAGATTTACACGTCATCGGA
ATTGATCGTGGAGAGCGTAATCTTATCTACGTCAGCGTCATCGACACCTGTGGAAAC
ATTGTGGAACAAAAAAGTTTTAATATCGTAAACGGCTACGACTATCAAATTAAACTT
AAACAGCAAGAGGGAGCTCGCCAGATCGCTCGCAAAGAGTGGAAAGAGATTGGGA
AAATTAAAGAAATTAAAGAGGGTTACCTGTCGCTGGTAATTCACGAAATCTCGAAA
ATGGTCATCAAATATAATGCAATTATCGCTATGGAGGATCTGTCCTACGGGTTCAAG
AAGGGACGTTTTAAAGTAGAGCGCCAGGTGTATCAAAAATTCGAAACCATGTTGAT
CAATAAGCTTAACTATTTGGTCTTCAAAGATATTTCGATTACGGAGAACGGAGGTTT
GTTGAAAGGATATCAGCTGACGTATATCCCAGACAAGTTGAAAAACGTGGGGCATC
AATGTGGATGTATTTTCTATGTGCCCGCGGCCTACACGAGTAAGATCGATCCTACCA
CTGGTTTCGTCAACATTTTCAAATTTAAAGATCTTACCGTGGATGCGAAGCGCGAAT
TTATTAAGAAATTTGATAGCATTCGCTATGATTCCGAAAAGAACCTGTTCTGTTTTAC
GTTCGACTATAACAATTTCATTACCCAAAACACGGTGATGAGCAAATCCTCTTGGTC
AGTTTATACATACGGTGTACGTATCAAACGCCGTTTCGTTAACGGACGCTTTTCCAA
TGAGTCTGATACAATCGATATCACGAAAGATATGGAAAAAACATTAGAGATGACTG
ATATCAACTGGCGTGACGGGCACGACCTGCGTCAAGACATTATTGACTACGAGATTG
TGCAGCATATCTTCGAAATCTTTCGCTTAACTGTGCAAATGCGTAACTCGTTATCCGA
GTTAGAAGACCGTGACTACGATCGCCTGATTTCACCCGTCTTGAACGAAAATAACAT
CTTCTACGATTCCGCGAAGGCTGGGGACGCATTGCCCAAGGACGCAGACGCGAATG
GAGCGTACTGTATTGCGCTTAAAGGATTATATGAAATCAAGCAGATCACCGAAAATT
GGAAGGAGGACGGGAAGTTCTCACGCGACAAACTGAAGATTTCAAATAAGGACTGG
TTCGATTTCATTCAGAATAAGCGTTACCTGAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 70
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAATGGTA
CGAACAACTTTCAGAACTTCATCGGCATCTCCAGCCTTCAAAAGACTTTACGCAACG
CATTGATTCCCACGGAGACTACGCAACAGTTTATCGTAAAAAATGGTATTATCAAAG
AAGATGAATTACGCGGGGAGAATCGCCAGATTCTTAAGGACATTATGGACGATTAT
TACCGTGGATTCATCAGTGAGACACTGAGCTCCATTGATGACATCGACTGGACGTCA
TTGTTTGAAAAGATGGAAATCCAGTTGAAAAATGGCGATAACAAAGATACATTGAT
TAAAGAGCAGACAGAGTACCGCAAAGCAATTCACAAGAAATTCGCCAATGATGATC
GTTTTAAGAACATGTTTAGTGCCAAGCTTATTTCGGATATCTTACCCGAATTCGTGAT
TCACAACAACAATTATTCGGCAAGTGAGAAAGAGGAAAAGACCCAGGTTATCAAAT
TGTTTTCGCGCTTCGCCACTTCGTTCAAAGATTATTTCAAGAACCGTGCAAACTGTTT
CTCCGCTGACGACATCAGTTCCAGCTCATGCCACCGTATTGTAAATGACAATGCGGA
GATCTTTTTCAGTAATGCCTTAGTATATCGTCGCATTGTAAAGAGCTTATCTAATGAT
GACATTAACAAGATCTCGGGTGATATGAAGGACTCACTTAAGGAGATGAGTCTGGA
AGAGATCTACTCCTACGAAAAATACGGGGAATTCATCACCCAGGAGGGAATTTCAT
TCTACAACGATATCTGCGGCAAAGTTAACTCCTTTATGAATCTGTACTGTCAAAAGA
ACAAGGAGAATAAAAACCTGTATAAATTGCAGAAACTTCATAAACAAATTTTGTGT
ATCGCAGACACGAGTTATGAAGTACCTTATAAATTCGAATCCGACGAAGAGGTATA
TCAGTCCGTAAATGGGTTCCTGGACAATATCAGTAGTAAGCACATTGTGGAACGCTT
ACGCAAAATTGGAGACAATTACAACGGGTATAACCTGGACAAAATCTACATCGTAT
CCAAATTTTATGAAAGCGTGTCTCAAAAAACTTATCGTGATTGGGAAACAATCAACA
CGGCTCTTGAGATCCATTACAATAACATCTTGCCGGGTAACGGCAAATCGAAGGCA
GACAAAGTTAAAAAAGCAGTTAAGAACGACTTACAGAAAAGCATTACGGAGATTAA
CGAGTTAGTAAGTAATTACAAATTATGCTCCGACGATAATATCAAAGCTGAAACCTA
CATCCATGAAATTAGCCACATTTTGAACAATTTCGAAGCGCAGGAGCTGAAATATAA
CCCTGAAATCCATCTGGTAGAGTCTGAGTTGAAGGCGTCAGAACTGAAAAACGTTCT
TGACGTCATCATGAATGCCTTTCACTGGTGTAGTGTTTTTATGACTGAGGAGCTTGTA
GATAAGGACAACAACTTCTATGCTGAACTTGAAGAGATCTACGATGAAATCTACCCC
GTAATCAGTCTGTATAATTTAGTTCGTAACTACGTCACGCAGAAACCCTATTCGACT
AAGAAAATTAAGCTGAACTTTGGGATCCCTACTTTGGCAGACGGGTGGAGCAAGAG
TAAAGAATACAGTAATAATGCAATTATCTTGATGCGCGATAACTTATATTACTTAGG
TATTTTCAATGCTAAGAACAAACCTGATAAGAAGATTATCGAAGGAAATACGAGTG
AGAATAAGGGAGACTACAAAAAGATGATTTACAACTTGCTGCCAGGGCCTAATAAG
ATGATTCCAAAAGTTTTTCTGTCGAGCAAGACAGGGGTTGAAACTTATAAGCCATCC
GCTTATATCCTTGAGGGGTACAAGCAGAATAAGCATATCAAGTCCTCCAAAGATTTT
GATATTACATTTTGCCACGACTTAATTGATTACTTCAAGAACTGCATCGCAATCCATC
CCGAATGGAAGAATTTCGGCTTCGATTTCTCAGATACGTCCACGTATGAGGATATCT
CAGGCTTTTACCGCGAAGTTGAGCTGCAAGGTTATAAAATTGATTGGACATACATCT
CCGAAAAAGACATTGATCTTTTACAGGAAAAGGGCCAATTATACTTATTTCAAATCT
ATAACAAAGATTTTAGCAAGAAGTCCACAGGTAATGATAACCTGCATACGATGTATT
TGAAAAATCTTTTCAGTGAAGAGAATTTGAAGGATATCGTCCTGAAGCTGAACGGTG
AGGCTGAGATCTTCTTCCGCAAATCGTCTATCAAAAACCCCATCATTCACAAAAAGG
GAAGTATCTTAGTAAACCGCACTTATGAAGCGGAGGAAAAGGATCAGTTCGGGAAC
ATCCAGATCGTGCGCAAGAACATTCCAGAAAACATCTATCAGGAACTTTACAAATAT
TTCAATGACAAGTCTGATAAAGAATTATCAGACGAGGCGGCGAAACTTAAAAATGT
TGTTGGACACCACGAAGCAGCGACGAATATTGTAAAGGATTATCGCTACACATACG
ATAAATACTTTTTGCACATGCCAATCACCATTAACTTTAAGGCGAACAAGACAGGTT
TCATTAACGACCGTATTCTGCAATATATCGCAAAGGAAAAAGACCTGCACGTTATTG
GGATCGATCGTGGCGAACGCAATTTGATCTACGTAAGCGTTATCGACACTTGCGGAA
ATATCGTTGAACAAAAAAGCTTTAATATCGTCAATGGATACGATTACCAAATCAAGC
TGAAACAACAAGAAGGGGCACGTCAGATCGCTCGTAAAGAATGGAAAGAGATTGGT
AAGATCAAAGAGATTAAAGAAGGGTATCTTTCTTTAGTAATTCACGAGATTTCGAAA
ATGGTTATTAAATACAATGCGATTATTGCTATGGAAGACTTAAGCTACGGCTTTAAG
AAAGGTCGCTTCAAAGTGGAGCGCCAAGTGTATCAGAAGTTTGAAACGATGTTGAT
TAACAAATTAAATTACCTGGTCTTTAAGGACATCAGTATCACAGAAAATGGGGGGTT
GCTTAAAGGGTACCAGCTTACATACATCCCTGATAAACTGAAAAATGTCGGTCATCA
GTGCGGATGTATCTTCTATGTACCAGCAGCCTATACCAGTAAGATTGACCCTACTAC
TGGCTTTGTGAATATTTTTAAATTCAAGGATTTAACCGTGGACGCCAAGCGTGAATT
TATTAAAAAATTTGATTCGATTCGCTACGACAGTGAGAAAAACCTTTTCTGCTTTAC
CTTTGACTACAACAATTTTATTACCCAGAACACCGTAATGTCAAAGAGTTCGTGGTC
TGTATATACCTACGGTGTTCGCATCAAGCGCCGCTTCGTAAACGGGCGTTTCAGTAA
CGAATCTGACACCATCGACATCACTAAAGATATGGAGAAGACATTGGAAATGACGG
ACATTAATTGGCGTGATGGCCATGACTTACGTCAGGACATTATTGATTACGAAATTG
TGCAGCATATCTTCGAGATTTTCCGTTTGACAGTTCAGATGCGCAACTCACTGAGTG
AGTTAGAAGATCGCGATTACGACCGTCTGATCTCACCGGTCCTTAATGAAAACAACA
TTTTCTACGACTCAGCAAAGGCGGGTGATGCCCTGCCAAAGGATGCGGACGCTAAT
GGCGCCTACTGCATCGCCCTGAAAGGATTGTATGAAATTAAGCAGATTACAGAAAA
TTGGAAGGAAGATGGTAAATTTAGCCGTGATAAATTAAAAATCTCGAACAAGGATT
GGTTCGATTTTATTCAGAACAAACGTTATTTGAAACGTCCGGCAGCGACCAAAAAAG
CCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAA
GAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 71
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAATGGAA
CAAATAATTTTCAAAATTTTATCGGCATCTCAAGTCTTCAAAAAACCCTTCGCAATG
CCCTGATTCCAACTGAAACAACCCAGCAATTTATCGTCAAGAACGGCATCATTAAGG
AAGACGAGTTACGCGGGGAGAACCGTCAAATCCTGAAAGATATCATGGATGACTAC
TATCGTGGGTTCATTTCGGAAACCTTGTCTTCAATCGACGACATTGACTGGACGAGT
CTTTTCGAGAAAATGGAAATTCAGCTTAAAAATGGAGACAACAAGGATACTCTGAT
TAAGGAACAGACAGAATATCGCAAAGCTATCCACAAAAAGTTCGCTAATGATGATC
GTTTCAAAAATATGTTTTCTGCTAAATTGATTTCCGATATCTTGCCTGAATTTGTAAT
CCACAACAACAATTATTCTGCTTCCGAGAAGGAAGAGAAGACCCAGGTCATTAAAT
TATTCAGCCGCTTTGCAACCAGCTTTAAAGACTACTTTAAGAATCGCGCTAACTGCT
TTTCGGCGGATGACATCTCATCATCATCATGCCACCGCATTGTGAACGACAATGCGG
AGATCTTCTTTTCGAATGCGTTAGTTTATCGTCGCATTGTCAAAAGTCTTAGCAATGA
TGACATCAACAAGATCTCAGGAGACATGAAAGATTCCTTAAAGGAGATGTCTCTTG
AGGAAATCTATTCGTATGAGAAATACGGCGAGTTCATTACCCAGGAAGGTATTAGTT
TCTACAATGATATCTGCGGCAAAGTAAATTCTTTTATGAATCTGTATTGCCAAAAAA
ACAAAGAAAACAAGAATCTTTATAAGTTACAAAAGTTACATAAGCAAATTCTGTGC
ATCGCTGATACATCTTATGAGGTACCCTACAAATTTGAAAGTGATGAGGAGGTCTAT
CAGAGTGTCAACGGCTTCTTAGACAACATCTCTTCCAAACATATCGTGGAACGCCTG
CGTAAAATCGGAGATAACTACAACGGATATAACTTAGATAAAATCTACATCGTGTCC
AAGTTTTATGAAAGTGTGAGCCAAAAAACATATCGTGACTGGGAAACCATTAACAC
CGCATTGGAAATTCACTATAACAACATTTTGCCAGGCAACGGGAAAAGTAAGGCGG
ACAAAGTTAAGAAAGCAGTTAAAAATGACCTGCAAAAAAGCATCACTGAAATTAAC
GAATTGGTATCGAATTACAAATTATGTAGCGACGATAATATCAAAGCAGAAACTTA
CATTCACGAGATTAGTCACATTTTAAATAACTTCGAGGCCCAGGAATTGAAATACAA
TCCCGAAATTCATTTGGTTGAATCAGAACTGAAAGCATCAGAGTTGAAAAATGTGTT
AGATGTCATTATGAATGCGTTTCATTGGTGCTCTGTGTTCATGACCGAGGAACTGGT
TGATAAAGATAACAACTTTTACGCTGAATTGGAGGAGATTTACGATGAGATTTACCC
GGTCATTTCGCTTTATAACTTAGTGCGCAATTATGTGACGCAGAAACCATATTCCAC
GAAGAAAATCAAACTTAATTTTGGCATCCCTACTCTGGCTGATGGTTGGTCGAAATC
GAAAGAGTACAGCAACAACGCGATCATTCTTATGCGTGACAATCTTTACTATTTGGG
CATTTTTAATGCCAAGAATAAGCCAGATAAGAAAATCATTGAGGGGAATACTTCCG
AGAATAAGGGGGATTACAAAAAGATGATCTATAACTTGCTGCCCGGCCCCAACAAA
ATGATTCCTAAGGTTTTCTTGTCAAGCAAGACGGGCGTCGAAACATATAAGCCGTCA
GCTTATATTCTGGAAGGCTATAAACAGAATAAGCACATCAAGTCTTCCAAGGACTTT
GACATCACTTTTTGCCACGATTTGATCGACTACTTTAAGAACTGTATTGCGATTCATC
CGGAATGGAAGAACTTCGGTTTCGACTTTTCCGATACCTCAACATACGAGGATATCA
GCGGCTTCTACCGTGAAGTCGAGCTTCAAGGCTACAAGATCGATTGGACATATATTT
CAGAGAAGGACATTGATTTGTTACAAGAGAAAGGTCAACTTTACTTATTTCAGATCT
ATAACAAAGACTTTTCGAAGAAATCGACAGGAAACGATAACTTACACACTATGTAT
TTAAAAAATCTGTTTTCGGAGGAAAACCTGAAAGATATTGTGCTGAAACTTAACGGC
GAGGCAGAGATCTTTTTCCGTAAAAGCTCAATCAAGAATCCTATCATCCATAAAAAA
GGTAGTATTCTTGTCAACCGCACATATGAAGCGGAGGAGAAGGACCAATTCGGAAA
CATCCAAATTGTCCGTAAGAATATTCCGGAGAACATTTACCAAGAGTTGTATAAATA
CTTTAACGATAAGTCAGATAAGGAACTTAGCGATGAGGCGGCGAAGCTTAAAAACG
TAGTTGGGCATCATGAAGCTGCTACCAACATTGTAAAAGATTACCGTTACACCTATG
ACAAGTATTTCTTGCACATGCCCATTACGATCAATTTCAAAGCAAATAAGACAGGCT
TTATCAATGATCGCATCCTGCAGTACATTGCTAAAGAGAAGGATTTGCATGTTATCG
GTATTGATCGCGGAGAGCGCAATTTGATCTACGTCTCCGTAATCGACACTTGCGGTA
ACATTGTTGAGCAGAAGTCGTTCAACATCGTTAATGGTTATGATTACCAAATCAAGC
TGAAGCAGCAAGAGGGTGCCCGCCAGATCGCGCGTAAGGAATGGAAAGAAATCGG
GAAAATTAAAGAGATCAAAGAAGGCTATTTGTCTCTGGTAATTCACGAAATCAGCA
AGATGGTGATCAAGTATAACGCGATCATTGCGATGGAGGATCTTTCTTATGGCTTCA
AGAAAGGGCGCTTTAAAGTCGAACGCCAGGTCTACCAGAAATTTGAGACAATGCTT
ATCAACAAGCTTAACTATCTTGTATTTAAGGATATTTCCATCACTGAGAACGGAGGA
CTTTTAAAGGGGTACCAACTGACGTACATTCCTGATAAGCTGAAGAACGTTGGTCAT
CAATGCGGATGCATCTTCTATGTGCCAGCGGCTTACACCTCCAAAATCGATCCCACT
ACAGGCTTTGTCAATATCTTCAAATTCAAGGATTTGACCGTTGACGCGAAGCGCGAG
TTTATCAAGAAGTTTGATAGCATTCGCTACGACAGCGAAAAAAATTTATTTTGTTTT
ACTTTCGACTACAATAACTTTATTACTCAGAACACTGTCATGTCAAAGAGTTCGTGG
AGTGTCTACACGTACGGAGTACGTATTAAGCGCCGTTTCGTCAACGGACGCTTCTCA
AACGAAAGCGACACGATCGACATCACCAAAGACATGGAAAAAACTCTTGAGATGAC
GGATATCAATTGGCGCGACGGCCATGACCTGCGTCAGGATATCATTGATTACGAGAT
CGTTCAGCACATCTTCGAAATCTTCCGCCTTACCGTCCAGATGCGCAACAGTTTAAG
CGAGCTTGAAGACCGCGACTACGATCGTTTGATTAGCCCCGTTCTGAACGAGAATAA
TATTTTCTACGACAGCGCAAAGGCCGGTGATGCTTTGCCAAAGGACGCAGACGCGA
ATGGAGCCTACTGCATCGCCCTGAAGGGCTTATATGAGATTAAGCAAATTACCGAA
AATTGGAAGGAAGATGGTAAGTTCTCCCGTGATAAGCTTAAAATTAGCAATAAGGA
TTGGTTCGACTTCATCCAGAACAAACGTTACCTGAAACGTCCGGCAGCGACCAAAA
AAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAA
AAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 72
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGAA
CAAACAATTTCCAAAACTTCATCGGTATCTCTTCGTTGCAGAAGACTCTGCGTAATG
CTTTGATCCCGACGGAGACAACCCAACAATTTATCGTCAAAAACGGTATTATTAAGG
AGGACGAGTTACGTGGAGAAAATCGTCAAATCCTTAAGGACATCATGGACGATTAT
TATCGCGGGTTTATTTCTGAAACCCTGAGCAGTATCGATGATATCGACTGGACCTCA
CTTTTTGAGAAAATGGAGATCCAGTTGAAGAACGGTGATAACAAAGACACTCTGAT
CAAAGAGCAAACTGAATACCGCAAGGCAATTCACAAAAAGTTCGCCAACGACGACC
GTTTCAAGAATATGTTCTCAGCTAAGTTAATCAGCGACATTTTGCCAGAGTTCGTTAT
CCACAACAATAATTATAGTGCTTCAGAGAAGGAGGAAAAAACCCAAGTGATTAAAC
TTTTTTCGCGCTTTGCAACCTCATTCAAGGACTACTTCAAGAATCGCGCGAATTGCTT
CAGTGCGGACGACATTTCTTCTTCAAGTTGCCATCGTATCGTTAACGATAACGCGGA
AATTTTCTTCTCTAATGCTTTGGTGTATCGCCGCATTGTAAAATCGCTTAGTAACGAT
GACATTAATAAGATCTCAGGTGATATGAAAGATTCATTGAAGGAAATGAGCTTGGA
AGAGATTTACAGTTACGAAAAATATGGAGAATTTATTACTCAGGAAGGCATCTCATT
CTATAACGATATCTGCGGGAAGGTAAATTCGTTTATGAACTTATATTGCCAGAAAAA
TAAAGAGAATAAAAATTTGTATAAGCTTCAGAAGTTGCACAAACAGATCCTGTGCA
TTGCAGACACCTCGTATGAGGTTCCGTATAAATTTGAGTCCGATGAAGAAGTGTATC
AGTCTGTGAATGGTTTCTTAGATAATATCTCTTCCAAGCATATTGTCGAACGCCTGCG
CAAAATTGGTGATAACTATAACGGATACAATCTGGATAAAATTTACATCGTTTCTAA
ATTTTACGAGTCAGTCTCGCAGAAGACCTACCGCGACTGGGAAACAATTAACACGG
CATTGGAGATTCACTACAATAATATCTTGCCTGGTAACGGTAAGTCTAAGGCAGATA
AGGTAAAAAAAGCTGTGAAAAACGACCTTCAGAAAAGCATCACGGAGATTAATGAG
CTGGTGAGTAATTACAAATTATGTTCAGACGATAATATTAAAGCTGAAACGTATATC
CATGAAATCTCGCATATCTTGAACAACTTCGAGGCCCAAGAACTTAAATATAACCCC
GAAATCCATTTAGTCGAGTCTGAATTGAAAGCGTCGGAATTAAAAAACGTCTTAGAC
GTCATTATGAACGCGTTTCACTGGTGTTCAGTTTTCATGACCGAAGAGCTGGTCGAC
AAAGACAACAACTTCTATGCGGAATTGGAGGAAATCTATGATGAAATCTACCCTGTT
ATTTCACTGTATAACCTTGTGCGCAACTATGTCACTCAGAAGCCGTATTCGACCAAA
AAAATTAAATTGAATTTCGGTATCCCTACTCTTGCAGACGGATGGAGTAAAAGCAAG
GAATACAGTAATAACGCCATTATTCTTATGCGCGACAATTTATACTACCTGGGCATC
TTTAACGCAAAGAATAAGCCGGATAAGAAGATTATTGAGGGTAACACCAGTGAGAA
CAAGGGCGACTATAAGAAGATGATCTATAACTTATTGCCAGGTCCAAATAAAATGA
TCCCAAAAGTATTCTTATCATCAAAGACGGGAGTTGAAACCTATAAGCCTAGTGCCT
ATATTCTTGAGGGATATAAACAGAACAAGCACATTAAGTCGTCTAAGGATTTTGACA
TTACGTTCTGCCATGACTTAATCGACTATTTTAAAAACTGTATTGCGATTCACCCCGA
ATGGAAGAATTTTGGATTCGATTTTTCGGATACCTCGACCTATGAAGATATTTCGGG
ATTTTATCGTGAAGTGGAGTTGCAAGGCTATAAAATCGATTGGACCTATATCTCAGA
AAAAGACATTGATTTATTACAGGAAAAGGGACAACTGTACCTTTTCCAAATTTATAA
CAAGGACTTTTCTAAAAAGTCCACAGGAAATGATAACCTTCACACCATGTACCTGAA
GAACCTTTTCTCAGAGGAAAACCTGAAGGACATTGTCCTTAAGTTAAATGGAGAAG
CGGAGATCTTTTTCCGTAAATCTAGTATCAAGAATCCGATTATCCATAAAAAAGGTT
CGATTTTGGTAAATCGCACCTATGAAGCGGAAGAGAAAGATCAATTTGGTAACATC
CAGATCGTGCGCAAGAATATCCCGGAGAACATTTACCAAGAGCTGTATAAGTACTTC
AATGATAAGTCTGATAAGGAACTGTCAGATGAAGCTGCGAAATTGAAGAACGTGGT
TGGGCATCATGAAGCCGCTACCAATATCGTCAAGGATTACCGTTATACCTATGACAA
ATATTTCTTACACATGCCGATTACGATCAATTTTAAGGCAAACAAGACAGGATTCAT
CAACGACCGTATCTTGCAGTATATTGCCAAAGAGAAGGATCTGCATGTGATCGGTAT
TGACCGCGGGGAGCGCAATTTAATCTATGTATCGGTGATCGATACTTGTGGTAACAT
CGTAGAACAAAAGAGCTTTAACATCGTGAATGGTTACGACTATCAGATCAAGCTGA
AACAACAGGAAGGAGCCCGCCAGATCGCTCGCAAGGAATGGAAAGAAATCGGGAA
AATTAAGGAAATCAAGGAAGGCTACCTTTCATTGGTCATTCACGAAATTTCGAAAAT
GGTAATTAAGTACAACGCGATCATCGCCATGGAGGACCTTTCGTACGGATTTAAGAA
GGGTCGTTTCAAAGTTGAGCGCCAGGTATACCAAAAATTCGAGACTATGCTTATCAA
CAAACTTAACTACTTGGTCTTTAAGGACATTTCTATTACCGAAAACGGCGGCTTACT
TAAAGGCTATCAATTGACATATATTCCCGACAAACTGAAGAATGTTGGACATCAATG
CGGGTGTATTTTCTATGTGCCGGCAGCTTACACTAGTAAGATCGACCCTACAACCGG
GTTCGTAAACATTTTTAAATTCAAAGACTTAACAGTCGATGCGAAGCGTGAATTTAT
TAAGAAGTTTGATAGTATCCGCTATGACAGTGAAAAGAACTTGTTTTGCTTTACGTT
CGACTACAATAACTTTATTACACAGAACACGGTCATGTCTAAATCATCATGGTCGGT
TTACACATATGGGGTGCGCATCAAGCGTCGCTTTGTAAATGGCCGTTTTAGTAATGA
GAGCGACACAATCGACATCACAAAGGATATGGAGAAAACTCTTGAGATGACAGACA
TCAATTGGCGTGACGGTCATGACTTACGCCAAGATATCATCGACTACGAAATCGTAC
AGCATATTTTTGAGATTTTTCGTCTTACTGTGCAAATGCGTAATTCTTTATCCGAACT
GGAAGATCGTGATTACGACCGCTTGATTAGTCCCGTCTTAAATGAGAACAATATTTT
CTATGATTCTGCGAAAGCCGGAGATGCACTGCCCAAAGACGCTGATGCCAATGGCG
CGTATTGCATTGCATTAAAAGGATTATATGAGATTAAACAGATTACCGAAAATTGGA
AAGAGGACGGTAAATTCTCACGCGATAAATTGAAGATTTCTAACAAGGACTGGTTC
GACTTTATCCAAAATAAACGTTATCTTAAACGTCCGGCAGCGACCAAAAAAGCCGG
CCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAAA
CGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 73
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGTA
CCAACAACTTTCAGAATTTCATTGGCATTAGCTCGCTTCAAAAAACTTTACGCAATG
CTCTTATTCCGACTGAGACGACACAACAGTTTATCGTTAAGAATGGCATCATCAAAG
AAGATGAATTACGCGGAGAAAACCGCCAGATCCTGAAAGACATTATGGACGATTAT
TACCGTGGGTTCATCTCCGAGACGTTGTCATCGATCGATGACATCGACTGGACGTCA
CTTTTTGAAAAAATGGAGATCCAGTTAAAGAACGGTGACAATAAGGATACATTGAT
CAAAGAACAGACCGAGTACCGTAAAGCGATTCATAAAAAGTTTGCGAACGATGATC
GCTTCAAGAATATGTTTTCTGCGAAATTAATTTCCGACATTTTACCTGAATTTGTTAT
TCATAATAACAACTACTCGGCGTCTGAGAAAGAGGAGAAAACCCAAGTGATTAAAC
TTTTTTCACGTTTCGCAACGTCGTTCAAAGACTATTTTAAAAATCGTGCTAATTGCTT
TAGCGCGGATGACATCAGCTCTAGTTCATGTCATCGCATTGTCAACGATAATGCTGA
GATCTTTTTCAGTAATGCGTTAGTGTACCGTCGTATTGTGAAGTCCTTATCTAATGAT
GATATCAATAAGATCAGCGGGGATATGAAGGACTCACTTAAGGAGATGAGCTTGGA
GGAAATCTATTCCTATGAGAAGTATGGTGAGTTTATTACGCAAGAAGGAATTAGCTT
TTACAACGATATCTGTGGAAAGGTGAATTCGTTTATGAATTTGTATTGCCAGAAAAA
TAAGGAGAACAAGAACCTTTATAAATTGCAAAAGTTACACAAGCAAATCCTGTGCA
TTGCAGATACTTCCTACGAGGTGCCTTACAAGTTTGAATCCGACGAAGAGGTCTACC
AATCTGTAAACGGTTTCTTAGATAATATTAGTTCCAAGCATATTGTGGAGCGCCTTC
GTAAAATTGGCGATAATTACAACGGTTACAATTTAGACAAAATTTACATTGTCAGTA
AATTCTACGAGTCCGTATCTCAAAAGACGTATCGTGATTGGGAGACTATCAATACGG
CCCTGGAGATCCACTACAACAATATCTTGCCCGGTAATGGTAAGTCGAAGGCCGATA
AAGTTAAGAAAGCGGTGAAAAATGACTTACAGAAGTCAATCACCGAAATTAACGAA
TTGGTGTCCAATTATAAATTGTGTTCAGATGATAATATCAAAGCCGAGACCTACATT
CATGAGATTTCCCATATCTTAAATAATTTCGAGGCGCAAGAGCTTAAGTATAACCCA
GAAATCCACCTGGTAGAATCTGAGTTGAAGGCGTCAGAGTTAAAAAATGTTTTAGAT
GTCATTATGAACGCGTTTCACTGGTGCTCCGTATTTATGACGGAGGAATTAGTAGAT
AAAGACAACAATTTCTATGCCGAACTTGAGGAAATCTATGATGAGATCTATCCCGTC
ATTAGCCTGTATAACTTGGTCCGCAACTATGTTACCCAAAAACCGTACAGTACCAAG
AAGATTAAGCTGAATTTCGGCATTCCTACACTGGCTGATGGTTGGAGTAAATCGAAG
GAATATTCGAATAACGCGATTATCTTGATGCGCGACAACTTATACTATTTGGGGATC
TTTAACGCCAAAAACAAACCGGATAAGAAGATTATTGAGGGAAACACATCAGAGAA
CAAAGGCGACTACAAAAAAATGATTTACAACTTGTTACCGGGGCCTAACAAAATGA
TCCCGAAGGTGTTCTTATCCAGTAAAACAGGCGTTGAGACCTACAAACCTTCCGCAT
ACATCCTGGAAGGGTATAAGCAGAACAAGCACATTAAGTCCAGCAAGGATTTCGAT
ATTACCTTCTGTCATGATTTAATTGACTATTTCAAGAACTGTATTGCAATCCACCCCG
AGTGGAAGAACTTCGGATTCGACTTCTCAGATACGAGCACATATGAGGACATCTCG
GGGTTCTATCGTGAAGTAGAACTGCAGGGATATAAAATTGATTGGACATATATTTCC
GAAAAAGACATCGACCTTTTACAAGAGAAGGGTCAACTTTACTTGTTCCAAATTTAC
AATAAAGACTTCTCAAAAAAAAGCACGGGTAACGATAATTTACACACTATGTATTTA
AAGAACCTTTTCTCGGAAGAGAATTTAAAGGATATCGTATTGAAGTTGAATGGAGA
AGCGGAGATCTTCTTCCGTAAGTCCAGTATTAAAAACCCTATTATTCACAAGAAGGG
ATCGATTTTAGTTAACCGCACATACGAGGCCGAAGAGAAGGACCAATTTGGGAACA
TTCAAATTGTCCGCAAAAACATCCCTGAGAACATTTATCAAGAGCTTTATAAGTACT
TTAACGATAAGTCCGATAAGGAATTGTCAGATGAGGCGGCAAAGTTGAAGAATGTC
GTGGGGCATCATGAAGCTGCCACCAACATTGTGAAGGACTACCGCTACACTTACGA
CAAATACTTCCTGCACATGCCCATTACGATCAATTTTAAGGCCAATAAGACAGGCTT
TATTAACGACCGTATTCTTCAATATATCGCTAAGGAGAAGGACCTTCATGTGATTGG
GATCGACCGCGGAGAACGTAATTTAATTTATGTGTCCGTCATCGATACGTGTGGAAA
TATCGTGGAACAGAAATCATTCAATATCGTGAATGGCTATGATTACCAGATCAAATT
AAAACAGCAGGAGGGCGCTCGCCAAATTGCGCGTAAGGAATGGAAAGAGATCGGA
AAAATCAAAGAAATCAAAGAAGGATATTTGTCATTGGTGATCCATGAGATTTCAAA
AATGGTAATTAAATATAATGCAATTATCGCAATGGAAGACCTGTCCTATGGTTTTAA
GAAGGGTCGTTTCAAGGTAGAACGCCAAGTGTATCAAAAGTTCGAGACGATGCTGA
TCAATAAGCTGAATTATCTTGTGTTTAAGGACATTAGCATCACGGAAAATGGAGGGC
TGTTGAAAGGCTATCAACTGACGTATATCCCTGACAAGCTGAAAAATGTTGGCCATC
AGTGCGGGTGCATTTTCTACGTCCCCGCGGCGTATACAAGCAAGATCGATCCTACTA
CGGGATTCGTAAATATTTTTAAATTCAAAGACTTAACCGTGGACGCCAAGCGCGAAT
TCATTAAGAAGTTTGATAGCATTCGCTACGATTCAGAAAAAAATCTTTTCTGTTTTAC
GTTCGATTACAACAATTTTATCACCCAGAACACAGTGATGAGCAAGTCATCCTGGTC
TGTCTATACCTACGGTGTCCGTATCAAACGCCGCTTCGTCAACGGACGCTTCTCTAAT
GAATCTGATACCATTGACATCACCAAGGACATGGAAAAGACACTTGAGATGACAGA
TATTAACTGGCGTGACGGACATGACCTGCGTCAGGACATCATCGATTATGAGATTGT
TCAGCATATCTTCGAGATCTTCCGCCTGACAGTACAAATGCGCAATTCACTGTCAGA
ACTTGAAGACCGCGACTATGACCGCCTGATCTCTCCAGTATTAAATGAGAACAATAT
CTTTTATGACAGTGCTAAGGCCGGCGATGCCCTTCCGAAAGATGCTGATGCTAACGG
AGCTTATTGTATTGCATTAAAGGGTCTTTATGAGATCAAGCAAATTACCGAGAATTG
GAAGGAGGATGGCAAATTCTCGCGCGACAAACTGAAAATCAGTAACAAGGACTGGT
TCGATTTTATTCAGAATAAACGTTACCTGAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 74
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGAA
CGAACAACTTCCAGAACTTCATCGGCATCAGTTCTTTACAAAAAACCCTGCGTAACG
CCCTTATTCCGACTGAGACAACACAACAGTTCATCGTTAAAAACGGAATTATCAAAG
AGGACGAGTTGCGCGGCGAGAATCGCCAAATTTTGAAAGATATTATGGACGACTAT
TATCGTGGTTTTATTTCAGAAACACTGAGTTCGATTGACGATATCGATTGGACGAGC
CTGTTTGAGAAAATGGAAATCCAGTTGAAAAATGGCGATAATAAAGACACTTTAAT
CAAAGAACAAACCGAGTATCGTAAAGCGATCCATAAAAAGTTCGCTAATGACGATC
GTTTTAAGAATATGTTCAGTGCGAAACTGATTTCAGACATTTTGCCCGAGTTCGTGA
TCCATAATAACAACTATTCCGCCTCGGAAAAGGAAGAAAAAACCCAGGTGATTAAG
CTGTTCAGTCGCTTCGCAACATCTTTCAAGGATTATTTCAAGAATCGCGCGAATTGCT
TCAGTGCGGACGATATTTCTAGTTCAAGCTGCCATCGTATCGTTAATGATAACGCGG
AGATTTTTTTTAGCAATGCTCTGGTGTACCGCCGCATTGTTAAGTCACTGTCCAACGA
TGATATTAACAAGATCTCAGGAGACATGAAAGACTCGCTTAAAGAGATGAGTCTGG
AAGAGATCTATTCTTATGAGAAGTATGGCGAGTTTATTACCCAAGAAGGAATCTCAT
TCTACAATGATATTTGTGGAAAGGTGAACAGCTTTATGAATCTTTACTGCCAAAAAA
ACAAGGAGAATAAGAATCTTTACAAACTTCAGAAGTTACATAAACAGATTTTGTGTA
TTGCGGATACGTCTTATGAAGTCCCCTACAAATTTGAATCGGATGAAGAGGTATACC
AAAGTGTGAACGGATTCTTGGACAATATTTCTTCTAAACATATTGTTGAACGCTTAC
GTAAGATCGGGGATAACTACAATGGCTACAATCTTGACAAAATCTACATTGTTAGCA
AATTCTACGAGAGTGTCAGCCAAAAGACGTACCGCGATTGGGAAACAATTAATACT
GCGCTTGAGATTCACTATAATAACATTTTACCAGGCAACGGCAAGTCCAAGGCGGAT
AAAGTTAAAAAAGCTGTTAAAAACGATTTGCAAAAATCTATCACAGAAATTAACGA
GTTAGTTAGTAACTACAAACTGTGCTCCGATGACAACATTAAGGCTGAGACGTATAT
CCATGAGATCTCTCACATCTTAAACAATTTTGAAGCTCAAGAACTTAAGTACAATCC
GGAAATCCACCTGGTGGAATCCGAGCTGAAGGCTAGCGAACTGAAGAACGTATTGG
ACGTGATCATGAACGCGTTCCACTGGTGTTCTGTCTTTATGACGGAAGAGCTTGTCG
ACAAAGATAATAACTTTTACGCGGAACTTGAGGAAATTTACGATGAGATTTACCCAG
TTATTTCATTGTATAACCTTGTCCGTAATTACGTGACCCAAAAGCCTTATAGTACGAA
AAAAATCAAATTAAATTTTGGAATCCCAACACTGGCTGACGGTTGGAGCAAATCTA
AGGAGTATTCTAATAACGCAATCATCTTAATGCGTGACAACCTGTATTATTTGGGTA
TCTTCAATGCCAAAAATAAGCCTGACAAAAAGATTATCGAAGGAAATACTTCGGAG
AATAAGGGGGATTACAAAAAAATGATTTACAATTTGCTGCCCGGGCCGAACAAGAT
GATCCCCAAAGTGTTCTTATCCTCGAAGACTGGTGTAGAAACATACAAGCCAAGCGC
ATACATTCTGGAGGGTTACAAGCAAAACAAACACATCAAATCTTCAAAAGACTTTG
ACATTACATTTTGCCATGATCTTATTGACTACTTCAAAAACTGCATTGCTATTCACCC
CGAGTGGAAGAACTTTGGGTTTGACTTCAGCGACACGTCTACGTATGAGGACATCTC
CGGGTTCTACCGTGAAGTTGAGTTACAAGGGTATAAGATTGACTGGACGTATATTTC
AGAGAAAGATATCGATCTTTTGCAGGAAAAGGGCCAGTTATATTTATTCCAGATTTA
CAACAAGGACTTTAGTAAGAAGTCAACAGGAAATGACAACTTGCATACGATGTATT
TGAAAAATCTTTTTTCTGAGGAAAATCTTAAGGACATCGTACTGAAATTGAATGGCG
AGGCTGAAATCTTCTTCCGTAAATCCTCCATTAAGAATCCCATTATCCACAAAAAGG
GGTCTATCCTGGTGAATCGTACCTACGAGGCAGAGGAGAAGGATCAATTCGGAAAT
ATTCAGATTGTTCGTAAGAACATCCCCGAGAACATTTATCAAGAATTGTATAAGTAC
TTTAATGACAAATCTGACAAAGAGTTATCCGACGAAGCTGCGAAACTGAAAAACGT
TGTTGGTCACCACGAGGCCGCCACTAATATCGTAAAAGACTACCGTTATACCTATGA
CAAGTACTTTTTGCACATGCCGATCACTATCAACTTCAAGGCGAATAAGACGGGCTT
CATTAACGATCGTATCCTGCAATACATCGCCAAGGAGAAGGACCTTCACGTCATTGG
GATTGACCGTGGTGAGCGTAACCTGATTTATGTAAGCGTCATTGATACCTGCGGTAA
TATCGTCGAACAGAAAAGTTTCAACATTGTAAATGGATATGACTATCAGATCAAACT
TAAGCAGCAGGAGGGTGCACGCCAGATTGCCCGCAAGGAATGGAAGGAGATTGGG
AAGATTAAGGAAATTAAAGAAGGTTACTTATCACTGGTTATTCACGAGATCAGTAA
AATGGTAATCAAATATAACGCGATCATTGCCATGGAGGATCTGAGCTATGGCTTTAA
AAAGGGCCGTTTCAAAGTCGAGCGCCAGGTATATCAAAAGTTTGAAACAATGCTGA
TTAACAAATTAAACTATCTGGTTTTCAAAGATATTTCGATCACTGAAAATGGCGGGC
TGTTGAAGGGATACCAACTTACATACATCCCTGACAAACTGAAAAATGTCGGTCACC
AATGTGGATGTATCTTTTATGTACCAGCAGCGTATACGAGCAAAATCGATCCAACTA
CGGGTTTTGTGAACATCTTTAAGTTCAAGGATTTGACAGTAGATGCCAAACGCGAGT
TCATTAAAAAATTTGATTCAATTCGCTACGATTCAGAGAAAAATCTTTTTTGTTTCAC
GTTCGATTACAATAATTTCATTACGCAGAACACAGTAATGTCAAAGTCAAGCTGGTC
GGTCTACACGTATGGAGTCCGTATTAAACGTCGTTTTGTAAACGGCCGTTTCTCAAA
TGAATCAGATACAATTGATATTACGAAGGATATGGAGAAGACATTAGAGATGACTG
ACATTAACTGGCGCGACGGACATGATCTTCGTCAGGACATTATTGATTATGAGATTG
TACAGCATATCTTTGAGATCTTCCGCCTGACCGTTCAGATGCGCAATTCGTTGTCCGA
GTTAGAAGACCGCGATTACGACCGTTTAATCAGTCCCGTCTTAAACGAAAATAACAT
CTTCTACGATTCAGCCAAGGCAGGCGATGCCTTGCCAAAGGATGCTGACGCAAATG
GCGCATACTGTATTGCGTTGAAAGGCCTTTATGAAATCAAGCAAATTACCGAAAACT
GGAAAGAAGACGGAAAATTCTCCCGTGATAAGTTGAAAATCTCTAATAAGGATTGG
TTCGATTTCATCCAAAATAAACGCTATTTGAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 75
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGAA
CTAATAATTTCCAAAATTTTATAGGCATCTCTTCTTTACAGAAGACTCTTCGTAACGC
CCTAATCCCGACTGAGACCACACAACAATTCATAGTGAAAAATGGGATCATTAAAG
AAGACGAGCTGCGTGGGGAGAACAGGCAGATCCTAAAAGACATAATGGACGATTAT
TATAGAGGGTTCATCTCAGAGACATTATCTAGCATCGACGACATTGACTGGACCTCC
CTGTTTGAAAAAATGGAAATCCAGCTGAAGAATGGTGACAATAAAGACACATTAAT
AAAAGAACAAACAGAGTACAGGAAAGCCATCCACAAGAAGTTCGCAAACGATGAC
AGATTCAAAAATATGTTCAGTGCGAAGCTAATATCCGACATCTTACCAGAGTTTGTA
ATACACAATAACAATTACAGCGCGAGCGAAAAGGAAGAGAAAACGCAAGTAATTA
AGCTTTTTAGTAGGTTCGCTACCTCTTTCAAAGATTACTTCAAAAATCGTGCTAACTG
CTTCTCAGCCGACGACATATCTTCAAGTTCCTGTCACCGTATCGTGAATGATAACGC
TGAGATATTCTTCTCAAACGCCCTTGTATACCGTAGGATCGTAAAGTCCTTATCTAAC
GATGATATAAACAAGATCAGTGGAGACATGAAAGACAGCCTTAAAGAGATGTCTCT
AGAAGAAATTTACTCCTATGAAAAGTATGGGGAGTTTATAACACAGGAGGGGATCA
GCTTCTACAACGACATCTGCGGAAAGGTGAACAGTTTCATGAATCTTTACTGCCAGA
AGAATAAAGAGAACAAAAATCTTTATAAGCTTCAAAAGTTGCACAAACAAATACTG
TGCATTGCCGATACATCATATGAGGTCCCCTATAAGTTCGAATCTGATGAGGAAGTT
TATCAATCTGTTAACGGCTTTCTAGACAATATCAGCTCAAAACACATCGTAGAAAGA
CTGAGGAAAATAGGTGATAATTATAATGGATACAACTTGGATAAAATATATATAGT
CTCTAAATTTTACGAGTCAGTATCCCAGAAAACGTATAGGGATTGGGAGACCATCAA
CACGGCGTTAGAGATTCATTACAATAACATCTTACCGGGAAACGGAAAAAGTAAGG
CGGACAAAGTAAAGAAAGCCGTTAAAAATGACTTACAAAAGAGTATAACAGAAAT
AAACGAACTAGTAAGCAACTACAAGCTTTGTTCCGATGATAATATCAAGGCCGAGA
CATATATCCATGAGATCTCCCACATTCTAAACAATTTCGAAGCGCAAGAACTTAAAT
ATAATCCCGAAATCCACCTGGTGGAAAGTGAACTAAAGGCTAGTGAGTTAAAGAAC
GTTCTTGATGTTATCATGAACGCCTTCCATTGGTGCTCTGTTTTTATGACCGAGGAGT
TGGTTGATAAAGATAATAATTTCTACGCTGAATTAGAGGAGATATACGACGAAATCT
ACCCAGTGATTTCACTATACAACTTGGTCAGGAACTATGTTACACAAAAGCCGTACA
GCACTAAGAAAATTAAGCTAAATTTCGGTATCCCCACGTTAGCCGACGGGTGGAGC
AAGTCCAAAGAATATTCCAACAATGCGATTATTTTAATGCGTGACAATCTTTATTAC
CTTGGCATCTTCAATGCCAAAAACAAACCTGACAAAAAGATTATAGAAGGTAATAC
GTCCGAGAACAAAGGCGATTACAAGAAGATGATTTATAACCTACTGCCCGGACCAA
ACAAAATGATCCCCAAAGTTTTTCTTAGTTCTAAAACCGGCGTAGAGACGTATAAAC
CTTCTGCCTATATCTTAGAGGGATATAAGCAGAACAAACATATCAAATCTTCCAAGG
ACTTTGATATTACATTCTGCCACGATTTAATTGACTACTTCAAAAATTGCATAGCGAT
ACATCCGGAGTGGAAGAACTTTGGCTTCGACTTCAGTGATACATCCACCTATGAGGA
TATATCAGGCTTCTATCGTGAGGTCGAATTGCAAGGGTACAAAATCGATTGGACGTA
TATATCCGAGAAAGACATAGACCTTCTTCAAGAAAAGGGGCAGTTATATTTATTCCA
AATATACAACAAGGACTTCAGTAAGAAGTCAACAGGTAATGACAACTTACACACCA
TGTACTTGAAAAATTTATTTTCTGAAGAAAACCTAAAGGACATTGTACTAAAACTGA
ACGGGGAGGCAGAAATTTTTTTTAGAAAGAGCAGCATAAAAAACCCAATAATTCAT
AAGAAAGGAAGCATTTTAGTTAATAGGACGTACGAGGCAGAGGAAAAGGACCAGTT
TGGCAATATCCAGATCGTAAGGAAAAATATTCCTGAAAACATATATCAGGAACTAT
ATAAATACTTTAACGACAAATCCGACAAAGAATTATCCGACGAGGCTGCAAAGCTG
AAGAACGTCGTAGGGCACCATGAGGCAGCGACTAATATTGTGAAAGACTATAGGTA
TACATACGACAAATACTTTCTGCACATGCCCATCACGATTAACTTCAAGGCGAACAA
GACGGGATTCATTAACGACCGTATATTACAATATATTGCTAAGGAGAAAGATCTGCA
TGTAATAGGTATCGACAGAGGCGAACGTAATTTAATCTACGTGTCCGTCATCGACAC
GTGCGGGAACATCGTAGAGCAAAAGAGTTTTAATATAGTAAATGGCTATGATTACC
AAATTAAGCTAAAGCAGCAAGAAGGAGCAAGACAGATAGCTAGGAAAGAATGGAA
GGAGATAGGAAAAATAAAGGAGATCAAGGAGGGGTATCTTAGCCTAGTAATTCATG
AAATATCTAAGATGGTTATCAAATACAACGCTATCATAGCGATGGAAGACTTATCTT
ATGGTTTCAAGAAAGGAAGGTTCAAAGTAGAGCGTCAAGTTTATCAAAAGTTCGAA
ACGATGTTGATTAATAAACTAAACTATTTGGTATTTAAAGATATATCTATCACCGAG
AATGGTGGTCTACTAAAGGGTTACCAGCTTACATACATACCGGACAAACTTAAAAA
CGTCGGACATCAGTGTGGATGCATTTTCTACGTTCCAGCTGCATATACCAGCAAGAT
CGACCCAACGACTGGGTTCGTAAATATTTTTAAATTCAAGGATTTGACTGTCGACGC
CAAAAGAGAGTTCATAAAAAAGTTCGATTCAATTAGGTACGACAGCGAAAAGAATT
TGTTCTGCTTTACTTTTGACTATAACAATTTCATTACTCAGAACACTGTAATGTCTAA
GTCCTCTTGGTCAGTCTATACTTATGGCGTTCGTATCAAACGTAGATTTGTTAACGGT
AGATTCTCAAATGAAAGTGATACAATAGATATCACGAAAGATATGGAGAAAACATT
AGAAATGACAGACATAAACTGGAGAGACGGACATGACTTGAGACAGGACATTATTG
ACTACGAGATCGTGCAGCACATCTTTGAGATCTTTCGTTTGACCGTACAAATGCGTA
ACAGTTTATCTGAGCTTGAGGACAGGGACTACGATAGATTGATATCACCTGTATTAA
ATGAGAATAACATCTTCTATGATTCCGCAAAAGCAGGCGACGCTCTACCCAAAGAC
GCTGATGCGAACGGTGCTTATTGCATAGCTTTAAAGGGTTTGTATGAGATCAAACAG
ATAACAGAAAATTGGAAGGAAGATGGTAAGTTCTCCCGTGACAAGCTTAAAATATC
AAATAAGGACTGGTTCGATTTTATACAGAATAAGCGTTATTAAAACGTCCGGCAGCG
ACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCA
GCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCG
GGCTAA
SEQ ID NO: 76
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAATGGAA
CTAATAACTTCCAGAATTTCATTGGTATCTCCTCTTTACAAAAAACTCTAAGAAACG
CCCTAATTCCGACTGAAACTACACAGCAATTCATCGTCAAAAACGGGATCATTAAGG
AGGATGAGTTGAGGGGTGAAAATCGTCAAATTCTTAAAGACATCATGGACGACTAC
TACAGGGGGTTCATCAGCGAGACGTTATCTAGTATAGACGATATAGACTGGACTTCA
CTGTTCGAGAAGATGGAAATCCAATTAAAAAATGGGGACAATAAAGATACACTTAT
AAAGGAACAGACAGAGTATAGAAAGGCAATACACAAAAAGTTTGCCAACGACGAT
CGTTTCAAGAACATGTTTAGTGCTAAATTGATTTCAGATATTCTGCCGGAATTTGTTA
TTCACAACAATAATTATAGCGCCAGTGAGAAAGAAGAAAAAACGCAGGTTATCAAA
CTGTTCAGTCGTTTCGCTACATCTTTTAAGGATTACTTTAAAAACCGTGCAAATTGTT
TTTCAGCCGACGATATTAGTAGCAGCTCTTGTCACCGTATTGTTAATGATAATGCGG
AGATTTTCTTTTCAAACGCATTGGTCTACAGGAGGATAGTCAAGTCCCTTTCAAATG
ACGACATTAATAAGATCTCAGGTGACATGAAAGATTCCTTAAAGGAAATGTCCCTG
GAAGAGATCTATTCCTATGAAAAGTACGGTGAGTTCATTACTCAAGAGGGTATAAG
CTTTTACAATGACATATGTGGTAAGGTTAATAGCTTTATGAACCTGTATTGCCAGAA
GAACAAAGAAAATAAGAATCTGTATAAGTTGCAAAAGCTACACAAACAAATTTTGT
GCATTGCCGATACATCATACGAGGTGCCATACAAATTCGAGAGCGATGAGGAGGTT
TATCAGAGCGTGAATGGATTCCTGGACAATATTAGTAGTAAGCATATCGTGGAAAG
GCTTAGAAAGATAGGTGACAATTACAATGGCTACAATCTGGATAAAATCTACATCGT
CTCAAAATTCTATGAAAGTGTATCCCAGAAGACGTACCGTGATTGGGAAACTATCAA
CACCGCTCTGGAGATACATTACAACAATATACTTCCCGGAAACGGCAAGTCAAAAG
CCGACAAAGTCAAAAAAGCGGTCAAGAACGATTTACAAAAGTCTATCACTGAAATT
AATGAATTAGTTAGTAATTACAAACTGTGTAGTGATGATAATATTAAGGCAGAGACT
TACATACACGAAATTTCACACATTTTAAACAACTTCGAGGCACAGGAACTTAAATAT
AATCCTGAAATTCACCTGGTTGAAAGTGAATTGAAAGCCAGCGAGCTAAAGAACGT
TTTGGACGTAATCATGAACGCATTCCACTGGTGCTCTGTCTTTATGACAGAGGAACT
AGTGGATAAGGACAATAATTTTTATGCGGAGCTGGAGGAAATATACGATGAGATAT
ATCCCGTAATATCATTATATAATCTGGTAAGAAACTATGTGACTCAAAAGCCGTATA
GCACCAAGAAAATTAAACTTAATTTCGGCATACCCACTTTAGCGGACGGCTGGTCAA
AATCCAAAGAGTATAGTAATAATGCCATCATCCTGATGCGTGACAACCTGTACTATT
TAGGTATATTTAACGCCAAAAATAAACCCGACAAAAAGATTATAGAGGGCAACACC
TCAGAGAACAAAGGTGATTATAAGAAGATGATTTACAACCTTTTACCCGGTCCTAAT
AAGATGATTCCCAAAGTCTTTCTATCTAGCAAAACTGGTGTTGAAACATACAAACCC
TCAGCTTATATTTTAGAAGGGTATAAGCAGAATAAGCATATTAAAAGCTCCAAAGAT
TTCGATATTACCTTTTGCCATGACTTGATAGACTATTTCAAAAATTGTATTGCCATTC
ACCCTGAATGGAAAAACTTCGGATTTGACTTCTCTGACACATCCACCTACGAAGACA
TTTCAGGTTTTTACAGGGAAGTCGAGCTACAGGGTTATAAAATTGATTGGACATACA
TCAGCGAGAAAGATATTGACCTACTTCAAGAAAAAGGGCAGCTATACCTGTTCCAG
ATATACAATAAAGACTTCAGTAAAAAAAGCACCGGGAACGATAATCTTCACACAAT
GTACTTAAAAAATTTATTTAGTGAAGAGAATCTGAAGGATATAGTGCTGAAGTTAAA
CGGGGAGGCAGAGATATTTTTTAGAAAATCTAGTATTAAGAATCCGATCATCCACAA
GAAGGGTTCTATCCTTGTTAATAGGACTTATGAGGCAGAAGAAAAAGACCAATTCG
GCAACATACAAATTGTCCGTAAAAATATCCCTGAGAACATTTATCAGGAACTATACA
AGTACTTCAATGATAAAAGCGACAAGGAGCTGAGCGACGAGGCTGCTAAGTTAAAG
AATGTGGTGGGCCACCATGAGGCAGCAACGAATATTGTGAAGGACTATCGTTATAC
CTACGATAAATACTTTCTTCATATGCCGATCACCATTAATTTCAAGGCAAACAAAAC
TGGCTTCATTAACGATCGTATCTTACAATATATCGCAAAAGAGAAAGACCTTCACGT
TATCGGGATCGATAGAGGCGAGCGTAACCTAATTTATGTTTCTGTGATAGACACCTG
TGGGAACATAGTCGAACAGAAATCATTTAATATTGTTAACGGCTACGATTATCAGAT
AAAGTTGAAGCAACAAGAGGGTGCACGTCAAATAGCAAGGAAAGAATGGAAAGAA
ATAGGCAAGATTAAAGAAATAAAAGAAGGTTATTTATCCCTTGTAATACACGAAAT
TAGCAAAATGGTGATTAAATATAATGCGATCATTGCCATGGAGGATCTTTCTTACGG
CTTCAAAAAGGGGAGATTCAAAGTCGAGAGGCAGGTGTATCAGAAGTTTGAGACCA
TGCTAATCAATAAACTAAATTATCTAGTATTCAAAGACATAAGCATCACCGAAAATG
GCGGCTTGTTGAAGGGTTATCAATTGACCTACATCCCAGATAAACTAAAAAACGTAG
GGCATCAATGCGGATGTATATTTTACGTTCCAGCCGCATACACTTCCAAAATCGATC
CAACTACGGGTTTTGTGAACATCTTCAAATTCAAAGACTTGACTGTCGATGCTAAGA
GGGAGTTTATCAAGAAATTTGACTCCATTAGATACGACAGTGAGAAGAATCTGTTCT
GTTTTACCTTTGATTATAACAACTTTATAACTCAAAACACAGTCATGAGTAAGTCAT
CTTGGTCAGTGTATACGTATGGTGTGAGGATTAAAAGGAGGTTTGTTAACGGGAGAT
TTTCCAATGAAAGTGATACAATAGATATAACCAAGGACATGGAAAAGACTCTTGAA
ATGACCGACATTAACTGGAGAGATGGCCACGACTTACGTCAAGATATAATCGATTA
CGAGATAGTGCAACATATCTTTGAGATATTTAGGCTTACTGTCCAAATGCGTAACTC
ATTAAGTGAGTTGGAGGACAGGGATTACGATAGGCTAATAAGTCCTGTTCTTAACGA
AAACAATATATTCTACGATTCAGCAAAGGCGGGAGACGCCCTGCCCAAGGACGCGG
ATGCTAACGGCGCATACTGTATTGCCCTGAAAGGCTTGTACGAGATAAAACAGATC
ACGGAGAACTGGAAAGAAGATGGAAAATTCAGTCGTGACAAGTTAAAAATTAGTAA
CAAAGACTGGTTCGACTTTATTCAGAACAAGAGATATCTGAAACGTCCGGCAGCGA
CCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAG
CCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGG
GCTAA
SEQ ID NO: 77
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGAA
CCAATAACTTTCAAAACTTTATAGGCATCTCCAGTCTACAGAAGACACTACGTAACG
CTTTGATACCAACTGAGACCACGCAGCAGTTTATCGTCAAGAACGGTATTATAAAGG
AAGACGAGCTAAGGGGGGAAAACCGTCAGATCTTAAAGGACATCATGGATGACTAC
TACAGAGGCTTCATAAGTGAGACTTTGTCTAGTATAGACGACATCGACTGGACCAGT
TTATTTGAGAAGATGGAAATTCAGTTAAAGAACGGGGACAATAAAGACACACTAAT
TAAAGAGCAGACCGAATACAGAAAAGCTATACACAAAAAGTTTGCCAACGATGATA
GATTCAAAAATATGTTTTCAGCAAAATTGATTTCCGACATATTGCCAGAATTCGTAA
TCCATAATAACAATTATTCTGCAAGTGAGAAGGAAGAGAAGACCCAAGTAATCAAG
CTGTTTTCCCGTTTTGCTACGAGTTTCAAAGATTATTTCAAGAATAGGGCTAATTGTT
TCTCCGCGGACGACATAAGTAGCAGTTCCTGTCACAGGATTGTGAACGATAATGCTG
AGATATTTTTTTCCAATGCCCTAGTGTATAGGAGAATAGTTAAAAGCTTAAGCAACG
ACGATATCAATAAAATTTCAGGGGACATGAAGGACAGCTTAAAGGAAATGAGTTTG
GAGGAGATTTACAGTTATGAAAAATACGGAGAGTTTATAACTCAGGAAGGCATCTC
TTTCTATAATGATATCTGTGGGAAGGTAAACTCCTTCATGAATTTATATTGCCAGAA
GAATAAGGAAAACAAAAATCTTTACAAGCTTCAAAAGTTACATAAGCAGATCTTAT
GTATTGCCGACACGAGTTATGAAGTGCCTTATAAATTCGAGAGTGATGAGGAAGTGT
ATCAGTCTGTTAACGGATTCCTAGATAATATAAGTTCCAAACATATAGTCGAGAGGC
TGAGGAAGATTGGCGATAACTATAATGGATATAATCTTGACAAAATCTATATAGTCT
CTAAATTTTATGAAAGCGTCAGCCAGAAGACATATAGAGATTGGGAAACTATAAAC
ACAGCCCTTGAAATACATTACAATAACATCCTACCCGGCAATGGTAAGTCTAAGGCA
GACAAAGTTAAAAAAGCAGTAAAGAATGACTTACAGAAGTCAATCACGGAGATAA
ATGAGTTGGTCAGTAACTACAAATTATGCTCCGACGATAATATTAAGGCCGAAACAT
ATATACACGAGATAAGTCATATATTAAACAATTTCGAAGCCCAGGAGTTAAAATAT
AACCCTGAAATTCATCTGGTCGAAAGTGAGTTAAAGGCCAGTGAGTTAAAGAATGT
ACTTGACGTAATTATGAATGCTTTTCATTGGTGCTCCGTGTTCATGACCGAGGAGTTA
GTAGATAAAGACAATAACTTTTACGCCGAACTTGAAGAGATATACGACGAGATTTA
TCCGGTAATCAGCTTGTACAACTTAGTTAGAAATTATGTAACACAGAAGCCTTACTC
TACTAAAAAAATAAAACTGAACTTTGGTATCCCAACTCTTGCAGATGGTTGGAGTAA
AAGCAAGGAATATAGCAACAATGCGATCATCTTGATGAGAGACAACTTGTACTATTT
GGGAATCTTCAACGCGAAAAATAAACCCGACAAAAAAATCATCGAAGGGAATACCT
CTGAGAATAAAGGTGACTATAAGAAAATGATTTACAATCTACTTCCTGGTCCTAATA
AAATGATCCCGAAAGTGTTTCTTAGTTCTAAGACTGGTGTCGAGACGTACAAACCTA
GCGCGTACATCTTAGAAGGGTACAAGCAGAATAAACACATCAAATCAAGCAAAGAC
TTCGATATTACTTTTTGCCATGACTTGATAGACTACTTTAAAAACTGCATAGCAATCC
ACCCGGAGTGGAAAAACTTTGGCTTTGATTTCTCTGACACCTCTACATATGAGGACA
TATCTGGTTTTTACCGTGAGGTTGAATTGCAGGGATACAAAATTGACTGGACTTACA
TATCTGAAAAAGATATCGATCTATTGCAGGAGAAAGGCCAGCTTTACCTTTTCCAGA
TCTATAATAAGGACTTCTCTAAGAAGTCTACAGGGAATGATAATTTGCACACTATGT
ACTTAAAAAATCTGTTTTCCGAGGAAAACTTGAAAGACATTGTTTTAAAGTTGAACG
GAGAAGCTGAAATATTTTTCAGAAAGAGCTCCATAAAAAACCCGATCATTCATAAG
AAGGGATCTATCCTGGTTAACAGAACGTACGAAGCGGAAGAAAAAGACCAATTCGG
AAACATTCAAATTGTTAGAAAGAATATCCCTGAGAACATCTACCAGGAGTTATATAA
GTATTTTAATGATAAGTCAGATAAGGAACTATCTGACGAAGCGGCGAAGCTTAAAA
ATGTTGTAGGACACCATGAGGCTGCTACAAATATAGTCAAGGACTACCGTTATACCT
ACGATAAGTACTTTCTACACATGCCCATTACCATCAATTTTAAAGCTAATAAAACGG
GTTTTATCAACGATCGTATCCTACAATATATTGCGAAAGAGAAGGATTTGCATGTCA
TTGGCATTGATAGAGGTGAGAGGAACCTAATATACGTATCCGTGATTGATACGTGCG
GGAACATAGTTGAACAGAAATCATTTAATATAGTTAATGGGTACGACTATCAGATTA
AGCTAAAGCAACAAGAAGGCGCCAGGCAAATTGCCCGTAAAGAATGGAAAGAGAT
CGGGAAGATCAAGGAAATAAAAGAAGGATACCTTTCCCTGGTCATCCATGAAATTA
GCAAAATGGTGATTAAGTACAATGCCATAATCGCGATGGAGGACTTAAGCTACGGG
TTCAAAAAGGGGAGGTTTAAGGTGGAGAGGCAAGTGTACCAGAAATTTGAGACCAT
GCTAATCAACAAACTGAACTACCTAGTTTTTAAGGACATTTCAATTACAGAGAATGG
AGGACTTTTAAAGGGTTACCAACTAACGTATATACCAGATAAGTTGAAAAATGTCG
GTCACCAGTGTGGCTGCATCTTTTACGTTCCCGCCGCTTATACATCTAAAATTGATCC
AACCACAGGCTTTGTAAATATCTTTAAATTCAAAGATTTAACTGTGGATGCAAAAAG
AGAGTTTATCAAGAAATTCGATAGCATTCGTTATGATAGCGAGAAGAACCTGTTCTG
CTTTACTTTCGACTATAACAACTTTATAACTCAAAACACCGTGATGTCAAAAAGCTC
ATGGTCAGTCTACACCTATGGTGTAAGGATTAAAAGGCGTTTCGTGAATGGGAGATT
CTCCAATGAAAGTGACACGATCGACATAACAAAGGACATGGAGAAGACACTAGAG
ATGACTGATATTAATTGGAGAGACGGACACGATCTGCGTCAAGATATAATTGATTAT
GAGATAGTACAGCACATATTTGAGATCTTCCGTTTGACTGTCCAAATGCGTAATTCC
CTTTCTGAGCTGGAAGATAGGGACTATGATAGATTAATATCCCCTGTACTAAATGAG
AACAACATTTTCTATGATAGTGCAAAAGCCGGGGATGCATTGCCGAAAGACGCTGA
CGCTAATGGGGCGTACTGTATAGCTTTAAAGGGGCTTTACGAAATAAAGCAGATAA
CCGAAAACTGGAAGGAAGATGGCAAATTCTCAAGGGACAAACTTAAGATCTCTAAC
AAGGATTGGTTCGATTTTATACAAAACAAACGTTATTTGAAACGTCCGGCAGCGACC
AAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCC
CGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGG
CTAA
SEQ ID NO: 78
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAATGGTA
CAAACAACTTTCAGAATTTCATTGGGATCTCTAGCTTACAGAAGACCCTGAGGAATG
CGTTGATTCCAACTGAAACAACCCAGCAATTCATCGTGAAAAATGGGATAATCAAA
GAGGATGAGTTAAGGGGTGAAAACCGTCAAATATTGAAGGATATTATGGACGACTA
CTACCGTGGATTCATCTCAGAGACGTTGAGCAGCATTGACGACATAGACTGGACTAG
CCTTTTCGAGAAGATGGAAATTCAGTTAAAGAACGGAGATAACAAAGATACACTAA
TCAAGGAACAGACAGAATACAGAAAAGCAATTCATAAGAAATTCGCTAATGACGAT
CGTTTTAAAAACATGTTCTCTGCAAAATTAATTAGCGACATTCTGCCGGAATTCGTT
ATACATAATAATAACTACAGTGCTTCTGAAAAGGAAGAGAAAACTCAGGTAATAAA
ACTGTTCTCTCGTTTTGCCACATCCTTCAAAGACTACTTTAAAAATAGAGCGAACTG
CTTTAGCGCCGACGATATTAGTTCTTCCTCATGCCACAGGATTGTCAACGATAATGC
AGAGATATTCTTTTCTAACGCACTAGTCTACAGAAGGATTGTAAAGTCTTTGTCAAA
TGATGACATAAACAAGATTAGTGGAGATATGAAAGACTCTCTAAAGGAAATGAGCC
TTGAGGAGATATACTCTTATGAAAAGTACGGTGAGTTTATTACCCAAGAAGGCATTA
GTTTCTATAATGACATTTGTGGAAAAGTTAACAGTTTTATGAATCTATACTGTCAAA
AAAATAAGGAGAATAAAAATCTTTATAAGTTGCAAAAACTGCATAAGCAGATATTA
TGTATAGCAGACACGAGCTATGAGGTACCGTACAAGTTCGAGAGCGATGAGGAAGT
CTACCAATCTGTCAACGGATTTTTGGACAACATTTCTTCAAAACATATTGTGGAGAG
GCTTAGGAAAATAGGCGACAATTATAATGGATATAACTTAGATAAGATATATATTGT
TTCCAAATTCTACGAATCTGTAAGCCAGAAGACATACAGAGATTGGGAAACGATAA
ACACAGCCCTTGAAATTCACTATAACAACATACTACCTGGAAACGGCAAATCAAAG
GCCGACAAAGTTAAGAAGGCCGTAAAGAATGATTTACAGAAGAGCATAACGGAGAT
CAATGAGCTGGTGTCTAACTATAAATTGTGTAGCGATGACAACATAAAAGCCGAGA
CTTACATTCACGAAATTTCACACATACTTAACAACTTTGAAGCTCAGGAATTAAAGT
ATAATCCCGAAATACACCTTGTGGAGTCCGAACTAAAGGCTAGTGAGCTTAAGAAC
GTCCTAGACGTAATTATGAATGCCTTCCACTGGTGTAGTGTTTTTATGACCGAGGAA
CTTGTTGACAAAGATAATAATTTTTATGCAGAACTAGAAGAGATATACGATGAAATA
TACCCGGTGATCAGTTTGTACAATCTTGTCAGGAACTATGTGACACAAAAGCCCTAT
TCAACAAAGAAAATAAAACTTAATTTCGGAATTCCTACGTTAGCTGATGGCTGGTCT
AAATCCAAGGAATACAGCAACAACGCTATAATTCTGATGAGAGATAACTTGTACTA
TCTAGGCATCTTCAATGCCAAAAATAAGCCTGATAAGAAGATTATAGAGGGCAACA
CTTCAGAGAACAAGGGCGACTACAAGAAAATGATCTATAACCTATTGCCTGGCCCA
AACAAGATGATTCCGAAGGTCTTCCTATCATCCAAGACCGGCGTTGAGACATACAA
GCCATCAGCGTATATTTTAGAGGGGTACAAACAAAACAAGCACATAAAGTCTAGTA
AAGACTTCGATATAACATTTTGTCATGACTTAATTGACTACTTTAAGAATTGCATCGC
TATACACCCGGAATGGAAGAATTTCGGCTTCGACTTCTCTGATACATCTACCTACGA
GGACATTAGCGGGTTTTACCGTGAAGTCGAATTACAAGGGTATAAGATAGATTGGA
CGTACATCTCTGAGAAAGACATAGACTTGCTTCAGGAAAAGGGCCAGTTGTATCTAT
TCCAAATATACAATAAGGATTTTTCCAAGAAATCTACGGGTAATGACAATCTTCACA
CAATGTATCTTAAGAACCTTTTCTCAGAAGAGAACCTGAAGGACATTGTCTTAAAAC
TAAATGGCGAAGCTGAGATTTTTTTCAGGAAGTCTTCAATTAAGAACCCGATAATCC
ACAAGAAGGGGAGTATTCTTGTGAATAGAACTTACGAGGCCGAAGAAAAAGACCAA
TTTGGTAACATCCAGATAGTCAGAAAGAACATTCCAGAGAACATCTACCAAGAGCT
ATACAAATATTTCAACGACAAGTCCGATAAGGAACTGTCCGATGAGGCAGCCAAGT
TGAAGAATGTCGTGGGTCATCATGAAGCTGCTACTAACATTGTCAAGGACTATCGTT
ATACTTACGACAAGTATTTCCTACACATGCCGATAACAATTAATTTCAAGGCTAACA
AAACAGGCTTTATCAACGATCGTATCTTGCAGTACATAGCTAAGGAAAAGGATTTGC
ATGTGATTGGCATTGATAGAGGGGAGCGTAACTTGATATATGTGTCTGTCATAGACA
CGTGTGGCAACATCGTCGAACAGAAATCATTCAACATAGTAAACGGCTACGATTAC
CAAATTAAGCTGAAACAGCAAGAGGGTGCACGTCAAATTGCGCGTAAAGAGTGGAA
AGAAATTGGTAAAATCAAGGAAATTAAAGAAGGCTACTTGTCTCTTGTTATACATGA
AATTTCCAAGATGGTTATAAAGTATAACGCGATAATTGCTATGGAAGACTTATCATA
CGGGTTTAAAAAGGGGAGGTTCAAGGTAGAGAGGCAGGTCTATCAAAAGTTCGAGA
CGATGTTGATTAATAAACTAAACTATCTAGTGTTCAAAGATATCAGCATTACGGAGA
ACGGGGGGCTACTGAAAGGATATCAACTAACGTACATTCCCGATAAGTTAAAGAAC
GTTGGTCATCAATGTGGTTGCATCTTCTACGTGCCTGCTGCCTATACGTCCAAAATAG
ATCCAACTACTGGATTTGTTAACATCTTTAAATTCAAAGATTTAACCGTAGACGCCA
AAAGGGAATTTATAAAAAAATTTGACAGCATCCGTTACGATAGCGAAAAGAATCTG
TTCTGTTTTACTTTCGACTACAATAATTTCATCACGCAAAATACGGTAATGTCTAAGT
CAAGTTGGAGCGTCTACACGTATGGAGTCAGGATCAAGAGGCGTTTCGTAAATGGA
AGATTCTCTAATGAGTCAGATACTATAGACATCACGAAAGATATGGAGAAAACCTT
GGAGATGACGGATATTAACTGGCGTGATGGACACGATTTAAGACAGGACATTATTG
ACTATGAGATTGTGCAACACATCTTCGAAATATTCCGTCTAACAGTCCAAATGAGGA
ATAGCCTAAGTGAATTGGAGGACCGTGATTACGATAGGCTTATAAGTCCTGTCCTTA
ACGAAAACAATATTTTCTATGATAGTGCTAAGGCGGGGGACGCACTGCCTAAAGAC
GCAGATGCTAACGGGGCATACTGCATTGCGTTAAAGGGTCTGTACGAAATCAAGCA
GATTACGGAAAACTGGAAAGAGGATGGCAAGTTTAGCAGAGATAAGTTGAAGATAA
GTAACAAAGATTGGTTTGACTTTATTCAGAATAAAAGGTATTTAAAACGTCCGGCAG
CGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGG
CAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTC
CGGGCTAA
SEQ ID NO: 79
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGCA
CTAATAATTTCCAGAATTTCATCGGCATTAGCAGCTTACAAAAGACGTTGAGGAATG
CCTTAATACCCACAGAAACTACTCAACAATTTATAGTGAAGAATGGGATAATTAAG
GAAGACGAGTTGAGAGGTGAAAATAGGCAAATCTTGAAAGACATTATGGATGACTA
CTACAGGGGCTTCATTAGTGAAACGTTGTCTTCAATAGATGACATTGATTGGACTTC
TTTGTTTGAGAAGATGGAAATACAGTTAAAGAACGGCGACAATAAGGATACACTTA
TCAAAGAGCAAACAGAATATAGAAAAGCAATTCACAAAAAGTTTGCTAACGATGAT
AGGTTCAAGAACATGTTTAGCGCTAAACTAATATCAGACATCCTTCCCGAGTTCGTT
ATTCATAACAATAACTATAGTGCAAGTGAAAAAGAGGAGAAGACACAGGTGATTAA
GCTGTTCTCCAGATTCGCGACTTCTTTCAAAGATTACTTCAAAAACAGAGCCAACTG
TTTTTCAGCTGACGATATCTCTAGTAGTAGTTGTCACCGTATAGTGAACGATAACGC
TGAGATCTTCTTTAGCAATGCATTAGTGTATAGAAGGATAGTTAAGTCTCTAAGCAA
TGATGATATCAATAAAATTTCCGGAGACATGAAGGACTCCCTAAAGGAAATGTCCTT
AGAAGAGATCTACTCATATGAGAAATACGGGGAATTTATTACGCAGGAAGGGATCT
CCTTTTACAATGACATATGCGGGAAGGTCAACTCTTTCATGAACTTATACTGCCAAA
AGAACAAGGAGAACAAGAATTTATATAAACTTCAGAAACTTCACAAACAAATACTG
TGCATAGCCGATACCTCATATGAGGTTCCTTACAAATTTGAATCAGATGAAGAGGTA
TACCAATCCGTTAACGGCTTTCTTGACAATATTAGCTCAAAGCACATCGTGGAGAGG
TTGAGAAAGATTGGTGATAATTATAATGGCTACAATCTAGATAAGATATATATTGTT
AGCAAGTTCTACGAGTCTGTGTCCCAAAAAACATATAGGGATTGGGAGACAATTAA
TACTGCTCTAGAAATCCATTACAACAACATCCTTCCTGGAAATGGCAAGAGTAAGGC
CGACAAAGTCAAGAAAGCAGTGAAAAATGATCTGCAAAAATCAATTACTGAGATAA
ACGAGCTAGTATCTAATTACAAGCTTTGTAGCGACGATAACATTAAGGCAGAAACG
TACATACACGAGATTAGTCACATCTTAAATAATTTTGAAGCCCAAGAACTGAAATAT
AACCCTGAGATACACCTTGTTGAATCCGAGTTAAAGGCGTCTGAACTAAAAAACGT
GTTAGACGTTATTATGAATGCCTTCCACTGGTGTAGCGTCTTTATGACTGAGGAGTT
GGTTGATAAGGATAATAACTTTTACGCTGAATTGGAAGAAATTTATGACGAAATCTA
TCCTGTTATTTCTCTATATAATTTGGTGAGAAATTACGTAACGCAAAAGCCCTATAGT
ACGAAAAAAATAAAACTAAATTTCGGGATCCCTACCCTAGCCGACGGTTGGTCTAA
ATCCAAGGAGTACTCAAACAATGCAATAATATTGATGAGGGACAACCTGTACTACC
TAGGCATATTTAATGCCAAAAATAAGCCCGATAAAAAGATTATAGAAGGGAACACG
TCAGAAAATAAAGGAGACTATAAGAAAATGATCTACAACCTTTTGCCCGGCCCCAA
TAAAATGATCCCGAAGGTCTTCCTAAGTAGCAAGACTGGCGTAGAGACCTACAAAC
CATCTGCATACATTTTGGAGGGGTACAAGCAAAACAAGCACATAAAGAGTAGTAAG
GATTTTGACATTACATTCTGCCATGACTTAATTGACTACTTTAAAAATTGCATCGCAA
TTCACCCTGAATGGAAAAATTTTGGATTTGATTTCTCTGATACTTCAACATATGAGG
ATATTTCAGGGTTCTACAGGGAGGTCGAACTACAGGGTTACAAAATAGACTGGACG
TATATTTCTGAGAAAGATATAGATTTGCTTCAGGAAAAGGGTCAGCTATATCTGTTC
CAGATATATAATAAGGACTTCTCCAAAAAGAGTACCGGAAATGATAATCTGCACAC
AATGTACTTAAAAAACTTGTTCTCTGAGGAGAATCTAAAAGACATCGTACTAAAACT
TAACGGGGAGGCCGAAATTTTTTTTAGGAAGTCCAGCATCAAGAACCCGATTATTCA
TAAAAAAGGTAGCATTTTGGTGAACCGTACTTATGAGGCGGAAGAAAAAGACCAAT
TCGGTAATATTCAAATCGTTAGAAAGAACATCCCTGAGAACATTTATCAGGAACTAT
ACAAATACTTTAACGACAAATCAGATAAGGAGCTTTCTGATGAGGCAGCTAAATTG
AAAAATGTAGTGGGACATCACGAAGCAGCCACTAACATAGTGAAGGACTACAGATA
CACATACGATAAGTACTTCCTGCACATGCCTATTACAATTAACTTTAAAGCAAATAA
AACAGGGTTTATTAACGACAGAATCTTACAGTATATTGCCAAAGAAAAGGATCTGC
ATGTGATAGGAATAGACAGAGGAGAAAGAAACCTGATATACGTCTCCGTGATTGAT
ACATGTGGGAACATAGTAGAACAGAAGTCCTTTAACATTGTTAATGGGTACGATTAT
CAAATTAAATTAAAACAACAAGAAGGAGCACGTCAAATAGCTAGGAAAGAATGGA
AAGAGATAGGAAAAATTAAGGAAATTAAGGAGGGTTACCTGTCCCTTGTAATTCAT
GAAATATCCAAAATGGTAATTAAATATAACGCGATCATCGCGATGGAAGATCTAAG
CTACGGGTTCAAAAAAGGCAGGTTTAAGGTGGAGAGGCAAGTTTACCAAAAGTTCG
AGACAATGTTGATTAATAAGTTAAACTACTTAGTTTTCAAAGATATCTCCATAACCG
AGAATGGCGGGCTTTTAAAAGGGTACCAACTAACATATATCCCGGATAAATTGAAG
AACGTTGGACACCAGTGTGGCTGCATATTTTATGTACCCGCTGCGTATACTTCTAAA
ATTGACCCGACCACCGGGTTTGTAAACATATTCAAGTTTAAGGACCTAACAGTTGAC
GCCAAACGTGAGTTCATCAAGAAGTTCGATAGTATAAGGTATGACTCTGAGAAGAA
CCTTTTCTGCTTCACGTTTGACTATAATAATTTCATCACCCAAAATACAGTTATGTCA
AAAAGCTCTTGGTCAGTATATACGTATGGCGTAAGGATTAAGCGTAGGTTCGTGAAC
GGTAGATTTTCCAACGAGTCAGATACTATTGATATTACCAAGGATATGGAGAAGAC
ATTAGAAATGACAGATATAAATTGGAGGGATGGGCACGATCTAAGGCAAGATATCA
TTGATTACGAAATTGTTCAGCACATATTCGAGATATTCCGTCTTACAGTACAAATGC
GTAACAGCTTGTCTGAGTTGGAAGATCGTGACTATGACAGGTTGATATCACCGGTCT
TGAACGAGAACAATATATTCTACGACAGCGCTAAGGCGGGAGACGCTCTGCCTAAA
GACGCAGATGCCAATGGGGCGTACTGCATTGCCTTAAAAGGCTTATACGAGATTAA
ACAGATCACAGAGAACTGGAAAGAGGACGGCAAGTTTTCTAGAGATAAATTGAAAA
TCTCAAACAAAGACTGGTTCGATTTCATCCAAAACAAAAGATACCTTAAACGTCCGG
CAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGC
AGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTT
ATTCCGGGCTAA
SEQ ID NO: 80
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAATGGAA
CTAACAACTTCCAGAACTTTATCGGCATCTCTTCCCTCCAAAAGACACTGAGAAATG
CACTGATCCCAACCGAAACGACTCAACAATTTATTGTTAAGAACGGCATCATAAAA
GAAGACGAGCTTCGCGGCGAGAACCGCCAGATACTTAAGGATATTATGGACGATTA
TTACCGAGGCTTTATCAGCGAAACTCTTAGCTCTATTGATGATATCGACTGGACCTC
CCTCTTCGAAAAAATGGAGATACAGCTCAAGAACGGCGATAATAAAGACACCTTGA
TAAAGGAACAGACTGAGTACAGGAAAGCGATCCACAAGAAATTCGCGAACGACGA
CAGGTTTAAAAACATGTTCTCTGCAAAATTGATATCCGACATCTTGCCGGAATTTGT
GATACACAACAATAACTATAGCGCTTCAGAGAAAGAAGAGAAGACCCAAGTAATCA
AGTTGTTCAGCCGCTTCGCAACGTCTTTTAAAGATTACTTTAAGAACCGGGCCAATT
GTTTCTCCGCGGATGATATTAGCTCATCAAGTTGCCATCGAATTGTCAATGATAATG
CGGAGATCTTCTTCAGCAATGCGCTGGTCTACAGACGAATCGTAAAAAGTCTTTCAA
ATGACGACATCAATAAGATTAGTGGAGATATGAAGGATTCCCTTAAGGAAATGAGT
CTTGAAGAAATATACTCATACGAAAAGTACGGGGAATTTATTACCCAGGAGGGGAT
CTCCTTCTATAACGACATCTGTGGAAAAGTAAACTCATTCATGAACCTGTACTGTCA
GAAAAACAAAGAAAACAAAAATCTGTATAAACTCCAAAAATTGCACAAGCAAATAT
TGTGTATAGCGGACACATCATACGAGGTTCCATATAAGTTCGAAAGTGATGAAGAA
GTCTACCAATCAGTGAATGGGTTTCTGGACAACATTAGTTCCAAGCACATAGTTGAA
CGACTGCGAAAGATTGGTGACAATTACAACGGCTATAATTTGGACAAGATTTATATA
GTTAGCAAATTTTATGAATCCGTATCACAAAAGACTTATAGAGACTGGGAAACAATC
AACACGGCACTTGAGATCCATTATAACAATATTCTTCCAGGGAACGGCAAAAGCAA
GGCTGATAAGGTAAAAAAGGCCGTTAAGAATGATCTTCAAAAATCCATAACGGAGA
TCAACGAACTTGTAAGTAACTACAAATTGTGCTCTGACGACAATATAAAGGCTGAA
ACGTATATTCACGAGATTAGCCATATCCTGAATAACTTTGAGGCCCAAGAACTCAAG
TATAACCCGGAAATACATTTGGTAGAAAGCGAGCTTAAAGCGAGTGAGCTGAAAAA
CGTCCTCGATGTGATCATGAATGCTTTCCACTGGTGTAGTGTCTTTATGACTGAGGA
GTTGGTTGATAAAGACAATAATTTCTACGCTGAACTGGAAGAAATTTACGACGAAAT
CTATCCAGTGATCTCCCTCTATAACCTCGTTCGAAACTACGTGACGCAGAAACCTTA
TTCTACAAAGAAAATTAAGTTGAACTTCGGCATTCCTACACTTGCTGACGGATGGTC
CAAATCCAAAGAGTACTCAAACAACGCAATCATCCTCATGCGGGATAACCTTTATTA
TTTGGGCATTTTCAACGCCAAAAACAAACCTGATAAAAAGATAATTGAAGGCAATA
CGAGTGAGAACAAGGGCGACTACAAAAAAATGATATATAACTTGTTGCCAGGCCCC
AACAAGATGATTCCTAAAGTTTTTCTGTCTTCTAAGACTGGAGTTGAAACTTACAAA
CCCTCCGCCTACATTCTTGAAGGGTATAAACAGAATAAGCACATAAAGTCCTCAAAG
GATTTCGACATTACGTTTTGCCATGACCTCATCGACTATTTCAAGAACTGTATCGCCA
TACATCCGGAGTGGAAGAATTTTGGATTTGATTTCTCCGACACATCTACCTATGAAG
ACATAAGCGGTTTCTACCGGGAGGTCGAGCTTCAGGGCTATAAGATAGATTGGACA
TACATTAGTGAAAAAGATATCGATCTTCTGCAAGAAAAGGGACAACTTTACCTTTTT
CAGATTTATAATAAAGACTTTTCAAAAAAGTCCACAGGGAACGATAATCTGCACAC
CATGTATCTCAAGAATCTGTTTAGTGAAGAAAACCTTAAAGACATAGTTTTGAAGCT
TAACGGAGAGGCTGAGATTTTTTTTAGAAAGTCCTCAATTAAAAACCCTATAATACA
CAAGAAAGGCTCTATTCTTGTTAACAGGACATATGAAGCCGAGGAGAAAGATCAGT
TTGGCAATATCCAGATTGTTCGCAAGAATATCCCGGAAAATATATATCAGGAGCTGT
ATAAATACTTTAACGACAAGAGCGACAAGGAGCTGAGTGACGAGGCCGCGAAGCTT
AAGAATGTAGTAGGTCACCACGAAGCAGCCACCAATATCGTCAAAGACTATAGGTA
CACGTACGACAAGTACTTTTTGCACATGCCTATAACTATAAACTTCAAAGCTAATAA
AACTGGGTTTATTAATGACAGGATTCTCCAATACATCGCTAAAGAGAAGGATCTGCA
TGTAATTGGCATAGACAGAGGTGAGAGAAACTTGATATATGTCAGCGTAATAGACA
CATGTGGCAATATCGTGGAACAGAAGTCTTTTAACATCGTCAATGGTTACGACTACC
AAATTAAGTTGAAACAGCAGGAAGGCGCACGACAGATCGCACGAAAGGAATGGAA
AGAGATAGGCAAAATAAAAGAAATAAAGGAGGGCTATCTCAGTCTCGTTATACACG
AAATTTCAAAAATGGTTATTAAGTACAATGCAATCATAGCGATGGAGGATCTCAGTT
ATGGGTTCAAAAAGGGTCGGTTTAAAGTTGAGCGCCAAGTGTACCAAAAGTTCGAG
ACAATGCTGATTAACAAGCTGAACTACCTCGTCTTCAAAGATATAAGTATTACGGAG
AACGGTGGCCTTCTTAAAGGCTATCAACTTACTTACATCCCGGACAAGCTCAAAAAC
GTAGGGCACCAATGCGGGTGTATTTTCTATGTGCCTGCGGCATATACGTCAAAGATT
GACCCAACCACAGGATTCGTAAACATATTCAAGTTTAAGGACCTCACCGTTGATGCG
AAAAGGGAGTTCATTAAAAAATTTGATTCTATTCGATATGATAGTGAGAAAAATCTC
TTTTGTTTCACATTTGACTATAATAATTTTATTACTCAGAATACTGTCATGAGCAAGT
CATCTTGGTCAGTGTACACATACGGGGTGCGGATCAAACGCAGGTTCGTCAATGGTC
GCTTCTCAAACGAATCAGACACCATTGACATCACAAAGGACATGGAAAAAACCCTT
GAGATGACCGACATTAATTGGCGCGATGGTCATGATCTGCGGCAAGACATCATAGA
CTACGAAATCGTCCAACACATCTTTGAGATCTTTCGCTTGACGGTCCAAATGCGGAA
CTCCCTGTCCGAGCTCGAGGATAGAGATTATGATCGGCTGATATCTCCCGTGCTTAA
TGAAAATAACATCTTCTACGACTCCGCCAAGGCGGGTGATGCCCTGCCGAAGGATG
CGGATGCTAATGGCGCTTATTGCATTGCTCTTAAGGGGCTCTATGAGATAAAGCAGA
TCACGGAAAACTGGAAAGAAGACGGTAAGTTTAGTAGAGACAAGCTGAAGATCTCA
AATAAAGACTGGTTTGATTTCATACAGAACAAGCGGTACCTGAAACGTCCGGCAGC
GACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGC
AGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCC
GGGCTAA
SEQ ID NO: 81
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAATGGCA
CTAACAATTTTCAGAATTTCATCGGCATTTCAAGTCTGCAAAAAACTCTGAGGAATG
CTTTGATCCCTACTGAAACCACTCAGCAATTTATAGTCAAGAACGGTATAATTAAAG
AAGATGAACTCAGGGGTGAAAATAGACAAATACTCAAGGACATTATGGATGACTAT
TATAGAGGCTTCATCTCAGAGACTCTCTCATCAATAGATGATATCGATTGGACTAGC
CTTTTCGAGAAAATGGAGATTCAGTTGAAAAATGGTGATAACAAAGATACGTTGAT
AAAGGAACAGACCGAGTACAGGAAAGCCATTCATAAGAAATTTGCTAATGACGATA
GATTTAAGAATATGTTTAGTGCAAAACTGATTAGTGACATTCTGCCGGAGTTCGTTA
TCCATAATAATAACTACTCTGCATCCGAAAAGGAGGAAAAGACGCAAGTTATTAAA
CTGTTCAGCCGCTTCGCCACAAGCTTCAAGGACTACTTCAAAAATAGAGCCAACTGC
TTTTCTGCCGACGATATATCATCATCTTCATGCCATCGGATCGTTAACGATAACGCCG
AGATATTCTTCAGCAACGCCCTTGTATATCGAAGAATAGTCAAAAGTCTGAGTAATG
ATGATATTAATAAAATTAGCGGTGATATGAAAGACTCCCTGAAGGAAATGTCACTG
GAGGAAATTTATAGTTACGAAAAGTACGGCGAATTCATTACTCAAGAAGGCATATC
CTTCTATAACGACATTTGCGGAAAGGTCAACTCATTCATGAACCTTTATTGCCAGAA
GAATAAGGAGAATAAAAATCTTTACAAATTGCAAAAACTTCACAAACAAATTCTTT
GCATCGCGGATACGTCCTACGAAGTTCCTTACAAATTTGAATCCGATGAGGAAGTGT
ATCAGAGTGTCAATGGATTTTTGGATAATATCTCTTCAAAACATATTGTGGAGAGAT
TGCGCAAAATAGGTGATAACTACAATGGCTACAACCTGGACAAGATTTATATTGTTA
GCAAGTTCTATGAAAGTGTCAGTCAAAAGACCTACAGAGATTGGGAGACAATCAAC
ACGGCGCTCGAAATACACTACAATAACATCCTCCCCGGCAATGGGAAGAGTAAAGC
CGATAAGGTTAAAAAAGCTGTTAAGAACGACCTCCAGAAATCCATCACGGAAATAA
ACGAGCTGGTTTCCAACTATAAGCTGTGTAGCGATGATAATATTAAGGCTGAGACAT
ATATACATGAGATCAGCCACATTCTCAACAATTTCGAGGCACAGGAACTCAAATAC
AATCCCGAGATTCACTTGGTGGAAAGTGAGTTGAAGGCGTCAGAGCTTAAGAATGT
ACTTGACGTAATAATGAATGCTTTTCATTGGTGCTCCGTGTTCATGACTGAGGAACT
CGTGGATAAGGATAATAACTTTTATGCGGAGTTGGAAGAGATATACGATGAAATAT
ACCCGGTTATCTCACTGTATAATCTGGTCAGAAATTACGTGACCCAAAAGCCTTATA
GTACAAAAAAAATAAAGTTGAACTTCGGTATTCCGACATTGGCAGATGGTTGGTCCA
AAAGCAAAGAATACTCTAATAACGCCATTATATTGATGCGAGACAATTTGTATTACC
TTGGGATCTTTAACGCGAAAAACAAACCGGATAAGAAGATCATCGAAGGTAATACA
TCTGAGAATAAGGGGGATTACAAGAAGATGATTTATAATCTGTTGCCGGGGCCAAA
CAAGATGATTCCGAAGGTCTTTCTGTCATCTAAGACAGGAGTAGAGACCTACAAACC
TTCTGCGTACATTTTGGAAGGCTACAAACAGAACAAGCATATAAAATCTAGCAAGG
ACTTTGATATCACGTTTTGTCATGATCTGATAGATTATTTCAAAAACTGCATCGCTAT
ACATCCTGAGTGGAAGAATTTCGGCTTTGACTTTTCTGACACCAGCACATACGAAGA
CATCTCAGGTTTCTACCGGGAAGTCGAGCTCCAGGGGTACAAGATTGACTGGACATA
TATAAGTGAAAAAGACATCGACCTCCTCCAAGAGAAGGGCCAACTTTACCTGTTCCA
GATCTATAACAAAGACTTTTCTAAAAAGTCCACGGGTAACGACAACTTGCACACTAT
GTATCTGAAAAACTTGTTCTCTGAAGAGAACCTCAAGGACATCGTCCTGAAGCTTAA
CGGGGAGGCGGAGATCTTCTTTAGAAAGTCCTCTATCAAAAATCCCATTATCCATAA
AAAGGGCTCTATACTCGTTAATAGGACATATGAAGCGGAGGAAAAAGATCAATTTG
GGAACATCCAGATCGTCCGGAAAAATATACCTGAGAATATCTATCAAGAGCTGTAC
AAGTATTTTAATGATAAGTCAGACAAAGAGCTCAGTGATGAGGCGGCAAAGCTCAA
GAACGTGGTGGGGCATCATGAAGCTGCGACGAACATTGTCAAAGATTATAGATACA
CTTACGATAAATACTTCCTCCACATGCCGATAACGATTAACTTCAAAGCCAATAAGA
CGGGGTTTATAAATGATCGGATCCTTCAGTACATTGCGAAAGAGAAAGACCTCCATG
TGATCGGAATTGACCGAGGAGAAAGGAATCTGATTTACGTGTCCGTGATTGATACTT
GCGGGAATATAGTCGAGCAAAAGAGTTTCAACATAGTCAACGGGTATGACTATCAG
ATAAAGCTCAAACAGCAGGAAGGTGCGAGGCAAATTGCGCGCAAAGAGTGGAAGG
AGATAGGCAAGATTAAAGAAATCAAGGAAGGTTATCTCAGCTTGGTGATCCATGAA
ATATCTAAGATGGTTATAAAGTACAATGCCATAATAGCCATGGAGGATCTTTCCTAC
GGGTTTAAGAAGGGCCGATTTAAAGTGGAGCGACAAGTTTACCAGAAGTTCGAAAC
CATGTTGATTAACAAACTTAACTATTTGGTGTTCAAGGATATAAGTATAACCGAAAA
CGGCGGTTTGCTTAAGGGTTATCAGCTCACGTATATTCCTGATAAACTTAAAAACGT
TGGACACCAGTGTGGATGTATCTTCTACGTGCCAGCCGCTTACACTAGTAAGATAGA
TCCTACCACGGGGTTTGTGAATATTTTTAAGTTTAAAGACTTGACAGTCGACGCCAA
AAGGGAATTTATAAAAAAGTTTGATTCTATCCGCTACGATAGTGAAAAAAATCTCTT
TTGCTTTACTTTCGACTATAACAACTTCATTACGCAGAACACTGTCATGAGTAAGTCC
AGCTGGAGCGTCTACACATATGGCGTCCGAATTAAACGACGATTTGTAAACGGGCG
GTTTTCAAACGAATCTGACACGATAGACATTACCAAGGATATGGAGAAGACACTTG
AGATGACCGACATAAACTGGCGGGACGGTCACGATCTTCGGCAGGACATAATTGAT
TACGAAATCGTCCAGCATATATTCGAAATATTTCGACTTACAGTGCAAATGCGGAAC
AGTCTCTCTGAACTGGAAGATCGCGATTATGACCGGTTGATTTCTCCGGTCCTCAAT
GAAAATAACATATTTTATGATAGTGCTAAGGCAGGTGATGCGTTGCCAAAGGATGC
AGACGCTAATGGTGCCTATTGTATCGCGCTCAAGGGATTGTACGAGATAAAGCAAA
TTACGGAGAACTGGAAGGAGGATGGTAAGTTTAGCCGAGACAAGTTGAAGATTAGC
AATAAAGACTGGTTTGATTTTATCCAAAACAAGAGGTACCTGAAACGTCCGGCAGC
GACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGC
AGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCC
GGGCTAA
SEQ ID NO: 82
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGAA
CTAATAACTTTCAAAATTTCATAGGTATTTCAAGCTTGCAGAAGACCCTGAGGAATG
CCCTGATTCCAACCGAGACAACGCAGCAGTTCATAGTCAAAAATGGCATTATTAAG
GAAGATGAGCTGCGGGGGGAAAACCGACAGATACTCAAGGATATTATGGACGACTA
TTACCGGGGATTTATCTCAGAAACGCTGAGCAGTATTGATGACATCGATTGGACCAG
TCTTTTCGAGAAAATGGAAATTCAACTTAAGAATGGTGACAATAAAGACACTCTCAT
AAAGGAGCAAACTGAATACCGAAAAGCCATACACAAAAAGTTTGCCAACGATGACC
GCTTTAAAAACATGTTTTCAGCTAAGCTCATTAGCGACATTCTCCCCGAGTTTGTGAT
TCATAACAATAACTATAGCGCATCCGAGAAGGAGGAAAAAACCCAAGTTATCAAAT
TGTTCAGTAGATTCGCTACGAGCTTTAAAGATTACTTTAAAAACCGGGCTAACTGCT
TCAGTGCAGACGATATCAGCTCCTCATCCTGTCATCGCATCGTCAATGATAATGCTG
AGATCTTCTTTTCTAATGCACTGGTTTACCGCAGGATAGTTAAGTCTCTTAGTAACGA
CGACATCAACAAGATATCAGGAGATATGAAGGATTCCCTTAAAGAAATGAGTCTCG
AGGAGATATATTCTTATGAAAAATACGGCGAATTTATTACCCAAGAGGGCATTAGTT
TCTATAATGACATATGCGGAAAAGTTAATAGTTTTATGAATCTCTATTGTCAGAAGA
ATAAGGAGAATAAGAACCTCTACAAATTGCAGAAGTTGCACAAGCAAATTCTGTGT
ATCGCGGACACCTCTTACGAGGTCCCATATAAGTTCGAGAGTGATGAAGAAGTATA
CCAGAGCGTTAATGGGTTCCTGGACAACATCTCAAGTAAACACATAGTCGAAAGGC
TCCGAAAGATCGGTGATAACTATAACGGATATAATTTGGATAAAATTTATATAGTTA
GCAAATTTTACGAGAGCGTCAGTCAGAAGACCTACCGGGACTGGGAGACCATAAAC
ACAGCGCTGGAAATACATTATAACAACATACTGCCTGGGAACGGTAAGTCAAAGGC
AGACAAGGTTAAAAAGGCTGTGAAGAATGACCTGCAAAAATCAATTACAGAAATAA
ATGAGTTGGTAAGTAATTACAAACTTTGCAGCGATGATAATATAAAGGCAGAGACG
TACATACATGAAATATCTCATATCCTCAACAATTTCGAAGCCCAAGAACTGAAGTAC
AACCCGGAAATTCATCTTGTAGAGTCTGAGTTGAAGGCCTCCGAATTGAAAAACGTT
CTTGACGTAATTATGAATGCCTTCCACTGGTGCTCAGTATTCATGACGGAAGAGCTC
GTGGATAAAGACAACAATTTTTACGCTGAACTGGAAGAAATATATGACGAGATTTA
CCCCGTAATTTCACTCTACAACTTGGTACGAAATTACGTTACCCAAAAGCCATACTC
AACAAAAAAAATTAAACTGAACTTCGGGATACCCACCCTCGCAGATGGATGGTCAA
AGTCCAAAGAGTACAGTAACAATGCAATTATCCTGATGCGAGACAACCTTTATTACC
TCGGGATTTTCAACGCTAAAAATAAACCTGATAAAAAAATAATTGAGGGTAATACC
TCTGAAAACAAGGGGGATTATAAAAAGATGATATACAATCTGCTGCCTGGCCCGAA
CAAAATGATTCCTAAAGTCTTCTTGTCTTCCAAGACTGGAGTCGAAACCTACAAGCC
AAGTGCTTATATACTCGAAGGGTACAAACAAAATAAGCACATAAAATCCAGCAAGG
ATTTTGATATTACATTCTGCCACGATTTGATTGATTATTTTAAGAACTGTATAGCCAT
CCACCCAGAATGGAAGAATTTTGGTTTTGATTTTAGCGATACCTCAACATATGAGGA
TATCTCTGGCTTTTACCGCGAGGTAGAACTGCAAGGTTATAAGATCGATTGGACTTA
TATTTCTGAAAAGGACATAGATCTCCTGCAAGAGAAAGGGCAACTTTATTTGTTTCA
AATATACAACAAAGATTTTAGTAAGAAGAGTACTGGCAATGATAACCTTCACACTAT
GTATCTGAAGAACCTTTTTTCTGAGGAGAACTTGAAGGACATAGTCCTTAAACTCAA
TGGGGAAGCTGAAATATTCTTTCGCAAAAGCTCCATTAAAAACCCGATCATTCATAA
AAAGGGTTCCATCTTGGTAAACCGCACATACGAGGCGGAAGAAAAAGATCAGTTCG
GAAATATCCAGATCGTAAGGAAGAATATCCCCGAAAATATATACCAAGAGCTTTAC
AAATATTTTAACGATAAGTCAGACAAGGAACTGTCAGACGAAGCAGCCAAGTTGAA
GAATGTCGTAGGGCACCACGAAGCAGCTACAAACATAGTTAAAGATTATCGGTACA
CCTACGATAAATATTTCCTGCATATGCCAATAACCATAAACTTCAAAGCCAACAAAA
CAGGGTTCATCAATGACCGAATACTTCAGTATATAGCCAAGGAAAAAGACCTGCAT
GTTATAGGAATAGATAGAGGTGAGCGCAACTTGATATATGTCAGCGTGATAGACAC
CTGCGGAAATATCGTCGAGCAAAAAAGTTTCAACATTGTTAATGGCTACGATTACCA
AATTAAATTGAAGCAGCAAGAGGGGGCTCGGCAAATCGCGCGAAAGGAATGGAAA
GAAATCGGGAAGATTAAAGAAATTAAAGAGGGCTACCTGTCTCTTGTAATTCACGA
AATATCTAAGATGGTCATCAAGTATAATGCCATTATTGCGATGGAAGATCTGTCCTA
CGGATTTAAGAAAGGCAGGTTTAAAGTCGAAAGGCAGGTGTACCAGAAATTCGAGA
CCATGCTGATTAATAAGCTCAACTATCTCGTATTTAAGGATATTTCTATAACTGAAA
ATGGAGGGCTTCTCAAAGGATATCAACTCACATACATACCTGATAAGCTGAAGAAC
GTAGGCCACCAGTGTGGATGCATATTCTATGTACCAGCTGCATACACAAGCAAGATC
GATCCAACTACTGGGTTTGTCAATATCTTCAAATTTAAGGACTTGACGGTCGATGCC
AAACGGGAGTTCATCAAAAAGTTTGATAGTATTCGATATGATAGTGAGAAGAACTT
GTTTTGCTTCACATTTGACTACAACAATTTCATAACGCAAAATACGGTTATGTCTAA
ATCCTCATGGAGCGTCTACACTTACGGAGTGAGGATAAAGCGGCGCTTCGTAAATG
GCAGGTTTAGCAATGAATCCGACACGATTGACATAACCAAGGATATGGAGAAAACC
CTCGAGATGACCGATATAAATTGGCGGGATGGACACGATCTGCGACAAGACATAAT
CGATTATGAAATCGTGCAGCACATATTTGAGATATTCAGGCTTACGGTCCAAATGAG
AAATTCCCTTTCCGAACTTGAAGACCGCGATTACGACCGACTGATAAGCCCCGTTCT
GAACGAAAATAACATCTTCTACGACAGCGCTAAAGCGGGAGACGCGCTGCCGAAAG
ATGCGGACGCAAATGGAGCCTATTGTATCGCCTTGAAAGGGTTGTACGAGATCAAA
CAGATAACCGAGAATTGGAAGGAGGATGGGAAGTTTAGTCGAGACAAACTTAAAAT
AAGCAACAAGGACTGGTTCGACTTTATTCAAAACAAACGATATCTCAAACGTCCGG
CAGCGACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGC
AGGCAGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTT
ATTCCGGGCTAA
SEQ ID NO: 83
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAATGGTA
CTAACAATTTTCAAAACTTTATCGGCATCTCTTCACTTCAGAAAACTCTTCGGAACGC
CCTTATACCGACGGAGACAACGCAGCAGTTTATAGTTAAAAACGGGATCATTAAAG
AAGATGAACTCAGAGGGGAAAACAGGCAAATATTGAAGGACATTATGGACGATTAC
TACCGGGGGTTTATTTCAGAGACCCTTTCATCTATTGATGACATAGATTGGACCTCCC
TTTTCGAGAAAATGGAGATACAATTGAAAAACGGCGACAATAAAGATACACTTATC
AAGGAACAAACTGAGTATCGCAAGGCGATTCACAAGAAGTTTGCGAATGACGATCG
CTTTAAGAATATGTTTTCTGCGAAGCTCATAAGTGACATTCTGCCTGAATTTGTCATT
CATAACAACAATTATTCTGCTAGCGAAAAAGAGGAAAAAACTCAAGTCATTAAGCT
TTTTAGCAGGTTCGCTACTAGTTTTAAAGACTATTTTAAGAACCGGGCGAATTGCTTT
AGCGCTGACGACATATCATCCTCATCCTGTCATCGCATAGTCAATGATAATGCAGAA
ATATTCTTTTCTAATGCGCTCGTGTATCGGAGAATAGTGAAAAGCCTCTCTAACGAT
GACATTAACAAAATAAGCGGCGATATGAAGGATAGTCTGAAGGAAATGTCCCTCGA
AGAAATATACTCATACGAGAAGTACGGAGAATTTATCACCCAGGAAGGAATTAGTT
TTTACAACGACATCTGTGGTAAGGTTAACTCTTTTATGAATCTGTATTGTCAAAAGA
ATAAAGAAAATAAAAATCTTTATAAGCTCCAAAAGCTTCACAAACAAATCTTGTGC
ATTGCGGATACGTCATACGAAGTACCTTACAAATTTGAAAGCGACGAAGAGGTGTA
TCAGTCAGTGAATGGGTTCCTTGACAATATTTCTAGCAAACATATTGTGGAGCGACT
TCGAAAGATCGGTGATAATTACAATGGCTATAATTTGGATAAAATTTACATAGTTAG
TAAGTTTTATGAATCCGTCTCACAAAAGACGTACCGAGATTGGGAGACCATCAACAC
TGCTCTGGAGATTCATTACAATAATATATTGCCTGGGAATGGGAAGTCAAAGGCCGA
CAAGGTTAAAAAAGCCGTAAAAAACGATCTTCAAAAGTCCATTACCGAGATAAATG
AACTTGTATCCAACTATAAGTTGTGCTCTGACGATAATATTAAAGCAGAAACGTATA
TCCACGAAATAAGTCACATCCTGAACAACTTCGAAGCTCAAGAGCTCAAGTATAATC
CTGAAATTCATCTCGTCGAAAGCGAGCTGAAAGCATCCGAGTTGAAGAATGTGCTTG
ATGTGATCATGAACGCATTCCATTGGTGCAGTGTGTTCATGACCGAAGAACTTGTAG
ACAAAGACAACAACTTCTACGCTGAATTGGAAGAGATTTACGATGAAATTTACCCC
GTGATATCCCTCTATAATCTGGTAAGAAATTACGTCACGCAAAAACCATACAGTACC
AAGAAAATAAAGCTCAACTTTGGTATTCCGACGTTGGCAGATGGGTGGAGTAAGAG
CAAGGAGTATTCTAACAATGCAATCATCCTCATGCGCGACAATTTGTATTATCTGGG
GATCTTCAACGCGAAAAATAAGCCCGACAAAAAGATAATAGAAGGCAATACGTCCG
AGAACAAAGGGGACTATAAGAAAATGATTTATAACCTTCTTCCAGGACCCAACAAG
ATGATCCCAAAGGTTTTCTTGAGTTCAAAAACCGGCGTAGAAACTTATAAACCGTCC
GCCTACATTCTGGAAGGGTACAAGCAAAACAAGCACATTAAGTCATCTAAGGATTT
CGACATTACTTTTTGTCATGATTTGATAGACTACTTCAAAAATTGTATAGCGATACAT
CCGGAATGGAAAAATTTTGGGTTCGATTTTTCCGACACAAGTACTTATGAAGACATC
TCAGGGTTTTATAGGGAAGTTGAACTGCAAGGTTACAAAATAGACTGGACTTATATT
AGTGAGAAGGACATTGATTTGCTCCAGGAAAAGGGTCAATTGTATCTGTTCCAGATA
TATAACAAGGATTTCTCTAAAAAATCTACAGGTAACGACAATCTCCACACGATGTAC
CTCAAGAATCTCTTCAGCGAAGAGAATTTGAAGGATATCGTACTTAAGCTCAATGGA
GAAGCGGAAATATTCTTCAGAAAGTCCAGCATTAAGAATCCTATAATTCACAAGAA
AGGGTCAATTCTCGTAAACCGGACTTATGAGGCCGAAGAAAAAGATCAGTTTGGTA
ACATTCAGATTGTACGGAAAAACATTCCCGAGAACATCTATCAAGAACTGTATAAAT
ACTTTAATGATAAATCCGACAAGGAACTTTCTGACGAGGCTGCAAAATTGAAGAAC
GTAGTGGGACACCATGAGGCCGCAACCAATATAGTAAAGGATTACAGATACACTTA
TGATAAGTATTTCCTCCATATGCCGATCACGATTAATTTCAAGGCGAATAAAACCGG
CTTCATTAACGATCGCATTTTGCAATATATTGCGAAGGAAAAGGATTTGCACGTGAT
AGGTATAGACCGGGGTGAACGAAACTTGATTTACGTCTCTGTGATCGACACATGCGG
AAATATAGTTGAACAGAAGTCCTTTAATATTGTGAATGGTTACGACTACCAGATAAA
ATTGAAGCAACAGGAGGGCGCAAGACAGATAGCTCGCAAAGAGTGGAAGGAAATC
GGCAAGATCAAAGAAATAAAGGAGGGTTATCTTTCCCTGGTAATTCATGAAATTAG
CAAGATGGTTATTAAGTATAATGCTATAATAGCTATGGAGGACCTTTCCTATGGGTT
CAAGAAAGGTCGCTTCAAAGTGGAGCGACAAGTGTATCAAAAGTTCGAGACTATGT
TGATAAATAAATTGAATTATTTGGTTTTTAAAGACATTTCAATAACTGAGAACGGGG
GTCTCTTGAAGGGGTACCAATTGACTTATATTCCGGACAAGTTGAAGAATGTCGGAC
ACCAGTGTGGTTGCATTTTCTACGTGCCTGCCGCTTACACCTCAAAAATCGATCCGA
CCACTGGTTTTGTAAATATATTTAAATTCAAAGATCTCACCGTTGATGCCAAACGGG
AGTTTATCAAAAAATTCGATTCCATTCGCTACGACTCTGAGAAAAACCTTTTTTGTTT
CACGTTCGATTATAACAACTTTATAACCCAAAATACTGTAATGTCCAAGTCAAGTTG
GTCTGTCTATACTTACGGAGTAAGGATCAAGCGCCGCTTCGTTAATGGGAGATTCTC
AAACGAGTCTGATACCATAGACATAACTAAAGACATGGAAAAAACCCTGGAAATGA
CGGACATCAATTGGCGAGACGGGCATGATCTTCGACAGGACATAATAGATTACGAA
ATTGTTCAACACATTTTCGAGATATTTCGACTTACGGTTCAGATGAGGAATTCCCTTT
CCGAATTGGAAGACCGGGATTATGATCGACTTATATCTCCCGTGCTCAATGAAAACA
ATATTTTTTATGATTCAGCGAAAGCTGGGGACGCGCTGCCAAAAGATGCCGATGCCA
ATGGAGCATACTGTATCGCCCTGAAGGGTTTGTATGAGATTAAGCAAATTACTGAAA
ACTGGAAGGAAGATGGCAAGTTTTCTAGAGATAAGCTTAAGATTAGCAATAAGGAC
TGGTTTGACTTCATTCAAAATAAAAGGTATCTTAAACGTCCGGCAGCGACCAAAAAA
GCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAA
AGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 84
AGCCCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAATGGAA
CAAATAATTTTCAAAATTTTATTGGTATCAGTTCATTGCAAAAGACTTTGAGAAATG
CTTTGATCCCGACTGAGACCACACAGCAGTTCATCGTCAAAAATGGCATAATCAAGG
AAGACGAACTTAGGGGTGAGAATAGACAAATATTGAAGGACATCATGGATGACTAT
TATAGGGGGTTCATTTCCGAAACGCTCAGTAGTATTGATGACATTGACTGGACTAGT
CTTTTCGAGAAAATGGAAATTCAGCTTAAGAACGGGGACAATAAAGACACGCTGAT
CAAGGAGCAAACGGAATATAGGAAGGCGATCCATAAAAAATTCGCGAATGATGATC
GGTTTAAAAACATGTTTAGTGCCAAGTTGATCAGCGACATACTGCCCGAATTCGTGA
TCCACAACAATAATTACAGCGCCTCCGAAAAGGAGGAAAAAACTCAGGTCATTAAA
TTGTTTAGCCGATTCGCAACGAGTTTCAAAGATTATTTTAAGAACCGGGCCAACTGT
TTTTCAGCGGATGATATTAGCTCCAGCAGCTGCCATCGCATAGTAAATGATAACGCT
GAAATCTTTTTTAGCAACGCACTTGTCTACCGGAGGATTGTAAAATCACTGTCAAAT
GATGACATTAACAAAATATCTGGAGATATGAAGGACTCACTCAAAGAAATGAGCCT
GGAAGAAATATATTCATACGAAAAATACGGGGAGTTTATTACCCAGGAAGGTATCA
GTTTTTATAATGATATATGTGGAAAAGTTAATTCATTTATGAATCTTTACTGTCAAAA
AAATAAGGAGAACAAGAATTTGTACAAGCTCCAAAAACTTCATAAACAGATTCTGT
GCATCGCAGACACAAGTTATGAGGTACCGTACAAATTTGAGAGCGACGAAGAAGTT
TATCAGAGTGTGAATGGTTTCCTGGACAATATCTCTTCTAAACACATTGTTGAGAGG
CTTAGGAAGATCGGTGATAATTATAACGGCTATAATCTGGACAAAATTTATATTGTA
TCAAAGTTTTATGAATCAGTCTCTCAAAAGACGTATCGGGATTGGGAAACAATTAAC
ACGGCTCTGGAGATCCACTACAATAACATTCTGCCCGGCAACGGGAAGAGCAAAGC
TGATAAGGTCAAGAAGGCAGTCAAGAACGACCTTCAGAAGAGCATAACAGAAATTA
ACGAATTGGTCAGTAACTACAAACTGTGTAGTGATGACAACATAAAAGCCGAAACA
TACATCCATGAAATAAGCCATATCCTGAATAACTTCGAAGCCCAAGAACTTAAATAC
AATCCCGAGATTCATCTTGTCGAATCAGAACTCAAGGCGTCCGAGCTCAAAAATGTC
CTTGACGTGATAATGAATGCCTTCCACTGGTGCAGCGTATTCATGACGGAGGAGTTG
GTAGATAAAGACAACAACTTTTATGCCGAATTGGAAGAGATTTATGATGAGATTTAC
CCCGTTATTTCTCTGTACAACTTGGTTCGAAACTACGTAACACAAAAACCATACTCA
ACCAAAAAGATCAAACTCAATTTTGGCATACCTACATTGGCTGATGGTTGGTCCAAG
TCAAAGGAATATAGCAATAATGCAATAATTCTCATGCGAGATAACTTGTATTATTTG
GGGATCTTTAACGCTAAGAACAAACCAGATAAAAAGATAATCGAGGGGAACACAA
GTGAGAACAAGGGTGATTACAAAAAAATGATTTACAATCTGCTTCCTGGGCCTAAC
AAAATGATTCCGAAGGTGTTTCTTAGCTCTAAAACTGGAGTGGAGACGTATAAGCCT
TCCGCGTACATTCTCGAAGGCTACAAGCAAAATAAGCATATCAAGTCCAGTAAGGA
CTTCGACATCACTTTTTGCCACGATCTCATCGATTACTTTAAGAACTGTATCGCAATA
CACCCCGAGTGGAAAAACTTTGGTTTTGATTTTTCAGACACTAGTACCTACGAGGAC
ATTTCCGGCTTCTATCGAGAAGTCGAACTCCAGGGCTACAAAATCGATTGGACGTAC
ATTTCTGAGAAGGACATCGACTTGCTCCAAGAGAAAGGTCAACTTTACCTCTTCCAA
ATTTACAATAAAGACTTTTCAAAGAAGAGCACCGGTAATGACAACTTGCATACCATG
TATCTGAAGAACCTGTTTTCTGAGGAGAACCTCAAGGATATTGTATTGAAGTTGAAT
GGCGAAGCAGAAATATTTTTCCGAAAGTCATCTATCAAGAACCCCATTATACACAAA
AAAGGCTCTATCCTGGTGAACCGGACTTACGAGGCAGAGGAGAAGGATCAATTCGG
AAACATACAGATAGTCCGCAAAAACATCCCTGAGAATATCTATCAGGAACTCTATA
AGTACTTCAATGATAAATCAGACAAGGAGCTTAGCGACGAAGCAGCTAAACTTAAA
AACGTGGTTGGCCATCACGAGGCCGCTACCAACATAGTCAAAGACTACCGCTATACT
TATGACAAGTACTTTTTGCACATGCCCATAACAATTAATTTCAAAGCTAACAAAACA
GGGTTTATAAATGACAGAATCCTCCAATACATCGCCAAAGAGAAGGACCTCCATGT
AATCGGGATTGATAGAGGCGAACGGAACTTGATTTACGTTAGTGTCATTGATACCTG
TGGTAACATTGTCGAACAAAAGTCATTCAACATAGTCAATGGATATGATTATCAGAT
AAAACTCAAGCAACAAGAAGGCGCGAGGCAGATTGCCAGGAAGGAATGGAAAGAA
ATCGGGAAGATCAAGGAGATCAAGGAGGGTTACCTGTCCTTGGTGATACACGAGAT
TTCAAAAATGGTTATAAAATACAATGCCATTATCGCGATGGAGGATTTGTCTTATGG
ATTTAAGAAGGGGAGGTTCAAAGTCGAACGACAAGTCTATCAGAAGTTTGAAACAA
TGCTCATTAACAAGCTCAATTACCTTGTTTTCAAGGATATAAGCATCACTGAAAACG
GCGGACTCCTTAAGGGATATCAGCTGACTTATATCCCCGACAAGCTCAAGAACGTAG
GGCACCAATGCGGATGCATCTTTTACGTGCCTGCAGCATATACTTCAAAAATTGATC
CGACTACTGGCTTTGTTAACATTTTCAAGTTCAAGGATCTGACGGTAGACGCTAAGA
GAGAATTCATAAAAAAGTTTGACAGCATCAGGTACGATAGTGAAAAGAACCTTTTTT
GTTTTACCTTTGACTACAATAATTTTATTACGCAAAATACAGTTATGAGCAAATCAA
GTTGGAGCGTTTACACATATGGCGTTCGGATCAAGCGCAGATTCGTCAATGGTCGCT
TCTCAAATGAGAGCGATACAATCGATATAACGAAGGATATGGAGAAGACGCTTGAG
ATGACAGATATCAACTGGCGGGACGGACATGACCTTAGACAAGACATAATCGATTA
CGAAATAGTACAGCATATCTTTGAGATTTTTAGGCTTACAGTTCAGATGCGGAACTC
TCTTTCCGAACTGGAGGACCGGGATTATGATCGGTTGATCTCCCCAGTACTGAACGA
AAATAATATCTTTTACGATAGCGCGAAGGCTGGTGATGCACTCCCAAAAGACGCTG
ATGCGAACGGAGCTTATTGCATAGCCCTTAAAGGGCTTTACGAGATTAAACAAATA
ACAGAAAATTGGAAGGAAGATGGCAAATTTTCCCGCGACAAGTTGAAGATTAGTAA
CAAAGACTGGTTCGACTTCATTCAGAATAAACGCTACCTCAAACGTCCGGCAGCGAC
CAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGC
CCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGG
GCTAA
SEQ ID NO: 85
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGTACCAA
TAACTTCCAGAACTTCATCGGTATTTCTAGCCTGCAAAAGACCCTGCGTAACGCGCT
GATTCCGACCGAGACTACCCAGCAATTCATCGTGAAAAACGGTATCATTAAGGAAG
ATGAATTGCGCGGTGAGAATCGTCAGATTCTGAAAGATATCATGGATGACTACTATC
GCGGTTTCATTAGCGAAACCCTGTCGAGCATCGATGATATCGATTGGACGAGCCTCT
TCGAGAAAATGGAAATTCAACTGAAAAATGGTGACAACAAAGATACCCTGATTAAA
GAACAAACGGAATACCGCAAGGCAATCCATAAAAAGTTTGCGAATGACGACCGTTT
TAAGAATATGTTCTCGGCCAAGCTGATTTCCGACATCCTGCCAGAGTTCGTCATTCA
CAACAACAATTACAGCGCAAGCGAGAAAGAGGAAAAGACTCAGGTCATTAAGCTGT
TTAGCCGCTTTGCGACGTCCTTCAAAGACTACTTCAAGAATCGTGCGAATTGCTTTA
GCGCGGATGACATCTCTAGCTCTAGCTGTCACCGTATTGTTAACGACAATGCAGAGA
TTTTCTTCAGCAACGCCCTGGTGTATCGCCGTATTGTCAAGTCTCTGAGCAACGACG
ACATTAACAAGATCAGCGGCGACATGAAAGACAGCCTGAAAGAAATGTCTCTGGAA
GAAATCTACAGCTACGAGAAATATGGTGAGTTTATCACCCAAGAGGGCATTAGCTTC
TACAATGATATCTGTGGTAAGGTTAATAGCTTTATGAATCTGTACTGCCAGAAGAAT
AAAGAAAACAAGAACTTGTACAAGCTGCAAAAGCTGCATAAGCAAATTCTGTGCAT
CGCCGATACTAGCTATGAAGTTCCGTACAAGTTCGAGTCTGATGAAGAGGTGTATCA
GTCAGTCAACGGTTTTCTGGATAACATCAGCAGCAAGCACATCGTCGAGCGCCTGCG
CAAGATTGGTGACAACTACAATGGTTATAACCTGGACAAGATCTATATCGTGTCGAA
GTTTTACGAGAGCGTGTCCCAGAAAACGTACCGTGATTGGGAAACGATTAACACGG
CCTTGGAAATTCACTATAACAATATCCTGCCGGGCAACGGCAAGAGCAAAGCTGAC
AAAGTCAAAAAAGCTGTGAAAAACGATCTGCAAAAGTCCATCACCGAGATCAACGA
ACTGGTTAGCAACTATAAGCTGTGTAGCGACGACAACATTAAAGCTGAAACGTATA
TCCACGAAATCAGCCACATCCTGAATAACTTTGAGGCACAAGAACTGAAATACAAT
CCTGAGATCCATCTGGTAGAGAGCGAGCTGAAGGCAAGCGAGTTGAAAAACGTTCT
CGACGTTATCATGAATGCTTTCCACTGGTGTAGCGTGTTTATGACCGAAGAACTGGT
TGACAAAGATAACAATTTCTATGCAGAGCTGGAAGAAATCTATGATGAAATCTACC
CGGTCATCAGCCTGTATAACCTGGTTCGTAACTACGTGACGCAGAAGCCGTACAGCA
CCAAAAAGATCAAGCTGAACTTCGGTATTCCGACCTTGGCGGACGGTTGGAGCAAA
TCCAAAGAATACTCCAATAATGCGATTATTCTGATGCGTGATAATCTGTACTATCTG
GGTATCTTCAATGCGAAGAACAAGCCAGATAAAAAGATTATTGAAGGCAACACCAG
CGAGAATAAAGGCGACTACAAGAAAATGATCTACAACTTATTGCCGGGTCCGAACA
AGATGATCCCGAAAGTTTTTCTGAGCAGCAAGACCGGCGTTGAAACCTATAAGCCG
AGCGCGTACATTTTAGAGGGCTATAAACAAAACAAGCACATCAAGAGCAGCAAAGA
TTTTGATATTACGTTCTGCCACGACCTGATCGACTATTTCAAGAATTGTATTGCGATT
CACCCTGAGTGGAAGAACTTCGGTTTTGACTTTTCCGATACCTCCACCTATGAAGAT
ATTAGCGGTTTTTACCGTGAAGTCGAGTTGCAGGGTTATAAGATTGATTGGACTTAC
ATTTCCGAGAAAGACATCGACCTGTTGCAAGAGAAAGGTCAGCTGTACCTGTTTCAG
ATCTATAACAAAGATTTCAGCAAAAAGTCGACGGGCAATGATAATCTGCACACCAT
GTATCTGAAAAACCTGTTTAGCGAAGAGAACCTGAAAGACATTGTTCTTAAGCTGAA
TGGTGAGGCCGAGATCTTCTTCCGTAAAAGCTCCATTAAGAACCCGATTATCCACAA
AAAGGGCTCTATTCTGGTTAACCGCACGTACGAAGCGGAAGAGAAAGATCAATTTG
GTAACATCCAGATCGTGCGTAAGAATATCCCGGAGAACATTTACCAAGAACTGTAT
AAGTATTTCAATGACAAGAGCGATAAAGAATTGAGCGATGAAGCGGCAAAGCTGAA
AAACGTCGTTGGCCACCACGAAGCCGCGACGAATATCGTGAAAGATTATCGTTACA
CCTACGACAAGTACTTTCTGCACATGCCGATCACCATCAATTTCAAAGCGAATAAAA
CGGGTTTTATCAATGACCGTATCCTGCAGTACATTGCGAAAGAAAAAGATTTACACG
TGATTGGTATTGATCGCGGCGAGCGCAATCTGATTTACGTCAGCGTTATCGACACGT
GCGGCAATATTGTGGAGCAGAAAAGCTTCAATATCGTCAATGGTTACGACTACCAG
ATCAAACTGAAGCAACAAGAGGGCGCCCGCCAGATTGCGCGTAAAGAGTGGAAAG
AAATCGGTAAGATTAAAGAAATCAAGGAAGGCTACCTGTCCCTGGTGATCCATGAA
ATCAGCAAAATGGTGATCAAGTACAACGCTATCATTGCGATGGAAGATCTGAGCTA
CGGTTTTAAAAAGGGTCGCTTCAAAGTTGAGCGTCAAGTGTATCAGAAATTTGAGAC
TATGCTGATTAACAAGTTGAACTATCTGGTTTTTAAAGACATCAGCATTACCGAGAA
TGGTGGCCTGCTGAAGGGTTATCAACTGACCTATATTCCTGACAAGTTGAAAAATGT
TGGTCATCAGTGTGGTTGCATTTTCTACGTACCGGCAGCGTACACGAGCAAGATTGA
CCCGACCACGGGTTTCGTTAACATTTTCAAGTTTAAAGATTTGACCGTGGACGCCAA
GCGTGAGTTCATTAAAAAGTTCGACAGCATCAGATACGACTCTGAGAAGAATCTGTT
CTGCTTTACGTTCGACTACAATAACTTCATTACCCAAAATACCGTTATGAGCAAAAG
CTCCTGGAGCGTGTACACGTACGGCGTCCGTATCAAGCGTCGTTTTGTGAATGGTCG
CTTTTCCAACGAATCTGACACCATTGACATTACCAAAGATATGGAAAAGACCCTTGA
GATGACCGACATTAATTGGCGTGATGGCCATGACTTGCGCCAAGACATTATCGACTA
CGAAATTGTTCAGCACATCTTTGAGATTTTTCGTCTGACGGTCCAGATGCGCAACTC
GCTGAGCGAGTTGGAAGATCGTGACTATGACCGTCTGATTAGCCCGGTGCTGAATGA
AAACAATATCTTCTATGATAGCGCAAAGGCCGGTGACGCGCTGCCGAAAGATGCGG
ATGCTAACGGTGCATACTGCATTGCACTGAAGGGTCTGTACGAAATCAAACAGATC
ACCGAGAATTGGAAAGAGGATGGTAAGTTTAGCCGTGATAAGCTGAAGATTAGCAA
TAAAGACTGGTTCGACTTTATTCAAAACAAGCGCTATCTGAAACGTCCGGCAGCGAC
CAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGC
CCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGG
GCTAA
SEQ ID NO: 86
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGAACAA
ATAATTTTCAGAACTTTATTGGGATCAGTTCGCTTCAGAAAACGCTTCGTAATGCTCT
GATTCCCACAGAAACCACTCAGCAGTTTATCGTAAAGAATGGCATTATCAAGGAGG
ATGAATTACGCGGCGAGAACCGCCAAATCTTAAAAGATATCATGGACGACTACTAC
CGCGGTTTCATTAGCGAAACTCTTAGTTCAATTGACGACATTGACTGGACGTCCTTG
TTCGAAAAGATGGAGATTCAATTAAAGAACGGTGATAACAAGGATACGTTGATTAA
AGAACAGACGGAGTACCGTAAGGCTATCCACAAAAAATTTGCAAACGACGACCGCT
TTAAAAATATGTTTAGCGCAAAATTAATCTCCGACATCCTGCCTGAATTCGTCATCC
ATAACAATAACTATAGCGCCTCGGAAAAAGAAGAAAAAACGCAGGTTATTAAACTT
TTCTCGCGCTTTGCAACAAGCTTTAAGGATTACTTCAAAAATCGCGCCAATTGTTTTT
CAGCCGACGACATTAGCTCCAGTTCCTGCCACCGTATTGTGAATGACAACGCTGAGA
TTTTTTTTTCCAATGCGCTGGTTTATCGTCGTATTGTTAAGAGCCTTAGTAACGACGA
CATTAATAAAATTAGCGGTGATATGAAGGATAGCTTGAAAGAAATGAGTCTGGAAG
AGATCTATAGTTACGAGAAGTACGGCGAATTTATTACCCAGGAGGGCATTTCATTTT
ACAATGATATCTGTGGAAAAGTCAACTCCTTTATGAACTTGTATTGCCAAAAGAATA
AAGAAAACAAAAACCTGTACAAACTGCAAAAGTTACACAAGCAGATTTTGTGTATC
GCAGACACGTCATACGAAGTACCGTACAAGTTTGAGTCCGATGAAGAAGTGTACCA
AAGCGTTAATGGCTTTTTGGATAACATTTCGAGCAAACATATCGTAGAGCGTTTGCG
TAAGATTGGTGATAATTACAACGGTTACAATTTAGACAAAATCTATATCGTCTCTAA
GTTTTACGAAAGTGTTTCTCAGAAAACTTACCGCGATTGGGAGACGATCAACACTGC
GCTGGAGATTCATTACAATAATATCCTTCCAGGTAACGGTAAAAGCAAAGCTGATA
AGGTGAAAAAGGCGGTTAAAAATGACCTTCAAAAGTCTATCACAGAAATCAACGAA
TTGGTCAGCAATTATAAGCTTTGCAGTGACGATAACATTAAGGCCGAGACTTACATC
CATGAGATCTCTCACATTCTTAATAATTTTGAAGCGCAAGAGCTGAAATACAATCCT
GAAATCCATCTGGTCGAAAGTGAATTAAAAGCCTCCGAATTAAAAAATGTCTTGGA
CGTGATCATGAATGCGTTCCATTGGTGCTCAGTTTTTATGACGGAAGAGTTGGTGGA
CAAAGACAACAATTTTTACGCCGAGCTTGAGGAAATTTACGACGAAATTTACCCCGT
TATTTCGTTATACAACCTTGTGCGTAATTACGTTACACAAAAGCCCTATTCGACAAA
GAAAATCAAGTTAAATTTCGGGATTCCCACATTAGCTGATGGATGGTCCAAATCCAA
AGAATACTCGAATAACGCTATCATCCTTATGCGTGATAATTTGTACTACTTAGGCAT
CTTCAATGCGAAGAACAAACCTGACAAGAAAATTATCGAAGGAAACACTTCGGAGA
ACAAAGGTGATTATAAAAAGATGATCTACAACTTGCTTCCCGGGCCAAACAAAATG
ATTCCCAAGGTATTTTTGAGTTCTAAAACCGGTGTCGAAACTTACAAACCAAGTGCT
TATATTTTGGAAGGATACAAACAGAACAAACATATCAAGTCTTCGAAAGACTTCGAT
ATTACGTTCTGCCACGATCTGATCGATTACTTCAAGAACTGTATTGCTATTCACCCCG
AGTGGAAGAACTTTGGATTTGATTTCTCCGACACGTCCACTTATGAAGATATCTCTG
GCTTCTATCGCGAGGTTGAATTACAAGGGTATAAGATTGACTGGACTTATATTTCGG
AGAAGGATATCGATCTTTTGCAAGAAAAAGGGCAACTTTATTTATTTCAGATCTATA
ACAAGGACTTTTCAAAAAAGAGCACTGGAAATGACAATCTGCATACCATGTACCTT
AAGAACCTGTTCTCGGAAGAGAACCTGAAGGACATTGTACTTAAACTGAATGGAGA
GGCAGAGATCTTCTTTCGCAAATCAAGCATTAAGAACCCAATTATTCACAAAAAGG
GGAGTATCTTAGTAAATCGCACATATGAGGCTGAGGAAAAAGATCAGTTTGGTAAC
ATTCAGATCGTGCGTAAGAACATTCCTGAAAATATCTATCAGGAACTTTATAAGTAT
TTCAACGATAAAAGTGATAAAGAGCTGAGTGACGAAGCGGCTAAACTTAAGAATGT
TGTGGGACACCATGAGGCAGCAACCAATATTGTGAAGGATTATCGCTATACGTACG
ACAAATACTTTTTACACATGCCCATCACTATTAATTTTAAAGCTAATAAGACTGGCTT
CATTAACGATCGCATCCTGCAGTACATTGCTAAGGAAAAGGATCTTCACGTTATCGG
TATCGATCGCGGGGAGCGTAATCTTATCTACGTCTCTGTCATTGACACGTGTGGCAA
TATTGTGGAGCAAAAGTCCTTCAATATTGTTAACGGCTATGACTATCAGATTAAATT
GAAACAGCAGGAAGGTGCGCGTCAGATTGCCCGCAAGGAATGGAAGGAAATTGGC
AAGATCAAAGAAATTAAGGAGGGCTACTTAAGCTTAGTAATTCACGAAATTAGTAA
AATGGTTATCAAATACAACGCCATCATCGCGATGGAGGATCTTTCGTACGGGTTTAA
GAAAGGTCGTTTTAAAGTGGAGCGTCAGGTGTACCAGAAATTTGAAACTATGCTTAT
TAACAAACTTAACTACCTGGTTTTCAAGGATATCAGTATTACTGAAAACGGGGGGCT
GTTAAAAGGGTATCAATTAACTTACATTCCAGACAAATTAAAGAACGTTGGACATCA
GTGTGGCTGCATTTTTTATGTACCAGCTGCATACACTTCAAAGATCGATCCTACGACT
GGGTTCGTGAACATTTTTAAGTTTAAAGACTTGACGGTAGATGCCAAGCGCGAATTC
ATCAAGAAATTCGACAGCATTCGCTACGACTCTGAGAAAAATCTTTTCTGTTTCACA
TTCGATTATAACAATTTCATTACGCAGAACACAGTAATGTCCAAGTCTTCTTGGAGT
GTTTATACATATGGTGTCCGCATTAAGCGCCGTTTCGTCAACGGCCGCTTCAGTAAT
GAGAGCGATACTATTGACATCACAAAAGACATGGAAAAAACACTGGAAATGACCGA
CATCAATTGGCGTGACGGCCATGACTTACGTCAGGATATCATTGATTATGAGATCGT
TCAACACATCTTCGAAATCTTTCGCTTGACTGTTCAAATGCGCAATTCCTTGTCGGAA
TTGGAGGACCGTGATTATGACCGCTTAATTTCCCCCGTCTTAAATGAAAACAATATT
TTTTATGACTCTGCAAAAGCTGGAGATGCTCTGCCGAAAGACGCCGATGCAAATGG
GGCATATTGCATTGCTTTAAAGGGGCTTTACGAGATCAAGCAAATCACCGAAAACTG
GAAAGAGGATGGAAAGTTTTCGCGTGATAAACTGAAGATCTCTAACAAAGACTGGT
TCGACTTTATCCAGAACAAGCGTTATTTGAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 87
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGCACCA
ATAACTTCCAAAACTTCATCGGGATCTCTAGCCTTCAGAAGACGCTTCGCAATGCTC
TTATCCCAACTGAGACCACTCAACAATTTATTGTGAAGAATGGAATTATTAAAGAGG
ACGAACTGCGTGGCGAGAATCGTCAGATCTTAAAGGACATTATGGATGATTATTACC
GTGGATTCATCTCCGAAACATTATCGTCGATCGATGATATCGATTGGACTTCTCTGTT
CGAGAAAATGGAAATTCAATTGAAAAACGGAGATAATAAAGATACGCTTATCAAAG
AACAGACGGAATATCGTAAAGCGATTCATAAGAAATTCGCAAATGACGATCGTTTC
AAAAATATGTTCAGTGCCAAGCTTATTTCGGACATTTTACCTGAATTTGTAATTCATA
ATAATAACTACTCAGCAAGTGAGAAGGAGGAGAAAACCCAAGTTATTAAACTGTTC
TCTCGTTTCGCAACGTCCTTTAAAGATTACTTTAAAAACCGCGCGAATTGCTTTAGCG
CTGACGACATTTCCAGCTCATCCTGTCATCGCATCGTAAACGACAATGCGGAAATCT
TCTTCAGCAACGCCCTGGTTTACCGCCGCATCGTCAAAAGCTTATCGAATGACGACA
TCAATAAGATCTCAGGAGATATGAAGGACTCGCTTAAGGAGATGTCTCTGGAGGAA
ATTTATAGTTACGAAAAGTATGGAGAGTTCATTACCCAGGAGGGAATCTCGTTCTAC
AATGACATTTGCGGGAAGGTGAACTCCTTCATGAACTTATACTGCCAGAAAAACAA
AGAGAACAAAAATCTGTATAAATTGCAGAAATTACATAAACAGATTCTTTGTATTGC
TGACACTTCCTACGAAGTACCCTATAAATTCGAGTCAGATGAAGAAGTATACCAGTC
CGTGAACGGATTTCTGGACAATATCTCCTCAAAACACATCGTGGAACGCTTACGTAA
AATTGGCGATAATTATAATGGTTACAATCTTGACAAAATTTATATCGTATCTAAATTT
TACGAGAGTGTGAGCCAAAAGACCTACCGCGACTGGGAGACCATCAACACAGCTTT
AGAAATTCACTATAATAATATCTTACCCGGCAATGGTAAGAGCAAGGCTGACAAGG
TAAAAAAGGCCGTCAAGAATGATTTGCAGAAATCTATTACAGAAATTAATGAGTTA
GTCTCCAACTATAAGCTTTGTTCCGACGATAACATCAAAGCTGAGACATATATTCAT
GAGATTAGTCACATTCTTAACAACTTCGAGGCCCAGGAACTTAAGTACAATCCTGAA
ATTCATCTTGTCGAGTCTGAGCTGAAAGCTAGTGAATTGAAAAATGTTTTAGACGTT
ATTATGAACGCATTCCACTGGTGCTCTGTGTTTATGACAGAAGAACTGGTCGACAAG
GACAATAACTTCTATGCCGAACTTGAGGAAATCTACGATGAAATTTACCCTGTAATC
TCCTTGTATAATCTTGTACGTAATTACGTCACTCAAAAACCTTACAGCACGAAAAAA
ATTAAATTGAACTTCGGGATTCCTACACTTGCCGACGGGTGGTCTAAATCCAAGGAA
TATAGCAACAATGCCATTATTTTAATGCGCGACAATCTTTACTATTTAGGAATTTTTA
ACGCTAAGAACAAGCCCGATAAAAAGATTATTGAAGGAAACACGTCTGAAAATAAG
GGCGACTACAAAAAGATGATTTATAACCTTTTGCCCGGTCCAAACAAAATGATCCCA
AAGGTATTCCTGTCATCCAAAACAGGGGTTGAGACATATAAGCCCAGCGCATATATT
CTGGAAGGATACAAACAGAATAAACATATCAAAAGCAGCAAAGATTTTGACATTAC
TTTTTGCCACGATTTAATCGACTACTTCAAAAACTGTATCGCTATCCACCCTGAATGG
AAGAATTTCGGATTTGATTTCTCAGATACAAGTACGTATGAGGATATCAGCGGTTTC
TATCGCGAAGTTGAACTTCAAGGGTATAAAATTGACTGGACCTACATTAGTGAGAA
GGACATCGACCTGTTACAGGAAAAAGGCCAATTGTACTTGTTTCAGATCTACAATAA
GGATTTCTCAAAAAAATCGACCGGCAATGATAACTTGCACACCATGTACCTGAAGA
ACCTTTTTTCGGAGGAAAACCTTAAAGACATTGTCCTGAAGTTGAATGGAGAAGCGG
AGATTTTCTTTCGTAAGTCTTCCATTAAAAATCCAATTATTCATAAGAAGGGCAGCA
TCCTTGTGAACCGTACGTACGAGGCGGAAGAGAAGGACCAATTCGGTAACATTCAA
ATCGTCCGCAAGAACATCCCTGAAAATATTTATCAGGAGCTTTACAAGTATTTCAAT
GATAAGTCCGACAAGGAATTATCAGATGAGGCTGCGAAGTTGAAAAATGTTGTTGG
TCATCACGAGGCGGCGACGAATATTGTAAAGGATTATCGCTACACTTATGACAAGTA
CTTTCTGCACATGCCGATCACCATTAATTTCAAGGCGAACAAAACAGGATTTATTAA
TGACCGCATCTTACAATACATTGCCAAAGAAAAGGACTTACACGTTATTGGCATTGA
TCGTGGAGAACGCAACTTAATCTACGTAAGCGTTATTGACACTTGCGGGAATATCGT
AGAACAAAAGAGCTTCAACATCGTGAATGGTTACGATTACCAGATCAAGCTTAAGC
AGCAGGAGGGAGCGCGCCAGATCGCGCGCAAGGAATGGAAGGAGATTGGTAAGAT
CAAGGAAATCAAGGAAGGTTATCTGTCCTTGGTAATCCACGAAATTTCGAAAATGGT
TATCAAATACAATGCTATTATTGCAATGGAGGACTTGTCCTACGGCTTTAAAAAAGG
ACGCTTTAAGGTGGAGCGCCAGGTTTATCAAAAGTTTGAAACAATGCTGATTAACAA
GCTGAACTATTTGGTCTTTAAAGATATCTCCATCACCGAAAATGGTGGGCTTTTGAA
AGGCTATCAACTTACATATATCCCTGATAAGCTTAAGAATGTGGGTCATCAGTGCGG
GTGCATTTTTTATGTTCCTGCAGCCTACACGTCCAAAATCGATCCTACAACTGGATTT
GTTAATATCTTCAAATTTAAGGATCTTACCGTCGACGCGAAGCGCGAATTTATCAAG
AAATTCGATAGTATTCGTTATGATTCCGAAAAAAACCTTTTCTGTTTCACCTTTGATT
ATAATAACTTTATCACGCAAAATACTGTCATGAGCAAATCGAGTTGGTCTGTGTACA
CTTACGGAGTACGCATCAAGCGTCGTTTTGTTAATGGGCGCTTCAGTAACGAGTCAG
ACACGATTGATATCACAAAAGATATGGAGAAAACGCTGGAGATGACAGACATCAAT
TGGCGCGATGGTCATGACTTACGTCAAGACATTATCGATTATGAAATTGTCCAGCAT
ATCTTTGAGATCTTTCGTTTGACTGTTCAGATGCGCAACAGCCTGTCAGAATTGGAG
GATCGTGACTATGATCGCCTTATTTCTCCCGTCTTAAATGAGAACAATATCTTCTACG
ACTCAGCCAAGGCTGGAGATGCACTGCCAAAAGACGCCGACGCAAATGGGGCCTAC
TGTATTGCATTGAAGGGGTTGTACGAGATCAAACAGATTACAGAAAATTGGAAGGA
GGACGGTAAGTTCTCTCGTGATAAGCTGAAGATTTCTAACAAAGACTGGTTCGATTT
CATTCAGAACAAACGTTACCTGAAACGTCCGGCAGCGACCAAAAAAGCCGGCCAGG
CGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAAACGTAA
AGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 88
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGTACCA
ATAACTTTCAGAATTTCATTGGAATCAGCAGCTTACAGAAAACCCTGCGCAATGCAC
TTATCCCCACTGAGACAACCCAGCAGTTCATTGTAAAGAACGGGATTATTAAAGAA
GATGAGCTTCGCGGGGAGAATCGTCAGATCTTAAAGGATATTATGGACGATTACTAC
CGTGGCTTCATTTCGGAGACGCTGTCGTCGATCGACGACATCGACTGGACATCCTTG
TTTGAAAAGATGGAAATCCAACTGAAGAATGGCGATAACAAGGACACGTTAATCAA
AGAGCAGACGGAATACCGTAAAGCTATCCACAAAAAGTTCGCTAATGACGACCGCT
TTAAGAACATGTTCTCAGCAAAACTTATTAGCGATATTTTACCTGAATTTGTCATCCA
CAATAACAATTACTCCGCGAGTGAAAAAGAGGAGAAAACCCAGGTGATTAAGCTGT
TTTCCCGTTTTGCAACCAGTTTCAAGGACTATTTTAAGAATCGTGCTAATTGTTTCTC
TGCAGACGACATTTCCTCGTCGTCCTGCCATCGCATTGTTAATGATAATGCTGAAAT
CTTTTTTTCAAACGCACTTGTGTATCGTCGCATTGTCAAAAGCTTAAGTAATGACGAT
ATCAATAAGATCTCAGGAGACATGAAGGACTCCCTGAAAGAAATGTCATTGGAAGA
AATTTACTCTTATGAAAAGTATGGAGAATTTATTACGCAGGAGGGTATCAGCTTCTA
TAACGACATTTGTGGTAAAGTGAACAGCTTTATGAATCTTTATTGTCAAAAGAATAA
AGAGAACAAAAATCTGTACAAGCTGCAGAAATTGCATAAACAAATTCTGTGCATTG
CAGATACTTCGTATGAGGTTCCTTACAAATTCGAGTCGGATGAGGAGGTGTATCAAA
GCGTAAACGGATTTTTGGATAACATTAGTAGTAAGCATATTGTGGAACGCCTTCGCA
AGATTGGTGACAACTATAACGGATACAACTTAGACAAGATCTATATTGTCTCGAAGT
TTTACGAAAGTGTTTCCCAAAAGACTTATCGCGACTGGGAGACAATCAACACTGCGC
TGGAAATTCACTATAACAATATCTTGCCGGGGAACGGAAAAAGTAAGGCAGATAAG
GTGAAGAAAGCAGTCAAAAATGATCTGCAAAAAAGCATTACTGAAATTAACGAACT
TGTGTCAAATTACAAATTGTGTTCGGATGACAATATTAAAGCGGAAACGTATATCCA
CGAGATCTCGCACATTCTTAATAATTTCGAGGCGCAGGAATTAAAGTATAATCCTGA
GATCCATTTGGTGGAATCAGAACTTAAAGCTAGTGAACTGAAAAATGTCCTGGACGT
TATTATGAATGCATTTCACTGGTGTTCTGTCTTTATGACAGAAGAACTTGTCGACAA
AGACAACAACTTTTATGCGGAATTAGAAGAGATTTACGACGAAATTTATCCCGTTAT
TTCGTTATATAATTTAGTTCGTAATTACGTGACTCAGAAACCCTACAGCACAAAAAA
GATTAAATTAAACTTTGGGATTCCGACTCTTGCTGATGGATGGAGCAAGTCCAAGGA
GTACTCTAATAACGCCATTATCTTGATGCGTGACAACCTGTACTACCTGGGCATTTTT
AACGCTAAAAACAAACCCGACAAAAAGATCATTGAAGGGAACACCTCGGAAAATA
AGGGGGACTATAAAAAAATGATCTACAATCTGTTGCCAGGCCCAAATAAGATGATC
CCAAAGGTTTTTTTATCTTCCAAAACTGGCGTAGAAACTTACAAGCCGAGCGCATAC
ATCCTTGAAGGATATAAACAAAACAAACATATCAAAAGTTCAAAGGACTTCGATAT
TACGTTCTGCCATGATTTAATCGATTATTTCAAGAATTGCATCGCGATTCACCCAGA
GTGGAAAAACTTTGGGTTTGATTTTTCAGACACCAGCACTTACGAGGATATTAGTGG
ATTCTATCGTGAGGTTGAACTGCAGGGCTATAAAATTGACTGGACCTATATTTCTGA
AAAAGATATTGATCTGCTTCAGGAGAAAGGCCAATTGTACTTATTTCAAATCTATAA
CAAGGATTTCTCCAAGAAGTCCACGGGTAATGACAACTTACACACAATGTATCTGAA
GAATCTGTTTAGTGAGGAGAACTTGAAGGACATTGTGCTGAAGCTTAATGGCGAGG
CCGAAATCTTTTTTCGTAAGTCCTCCATTAAAAACCCTATTATCCATAAGAAAGGGA
GTATTCTTGTCAACCGCACGTATGAGGCCGAAGAAAAGGACCAATTCGGAAACATC
CAAATTGTCCGTAAAAATATTCCTGAGAACATTTACCAGGAGCTTTACAAGTATTTC
AACGACAAGAGTGATAAAGAACTTTCAGATGAGGCGGCGAAACTGAAGAATGTAGT
GGGGCACCACGAAGCTGCCACGAATATTGTAAAGGATTACCGTTACACCTACGACA
AGTACTTTTTGCATATGCCCATCACAATTAATTTTAAGGCCAATAAAACTGGTTTTAT
CAACGATCGTATCTTACAGTACATTGCTAAGGAAAAAGATCTGCACGTTATCGGTAT
CGATCGCGGGGAACGCAATCTGATTTATGTTAGTGTGATTGACACGTGCGGAAATAT
TGTTGAGCAGAAGAGCTTTAATATCGTAAATGGATATGACTATCAAATTAAACTGAA
GCAACAGGAAGGGGCCCGCCAGATTGCCCGCAAGGAGTGGAAAGAAATTGGAAAG
ATCAAGGAGATTAAAGAAGGGTACCTTTCCCTTGTTATCCACGAAATCTCGAAAATG
GTGATCAAGTACAATGCCATTATTGCTATGGAGGATCTGTCATATGGGTTTAAGAAA
GGCCGCTTTAAGGTGGAACGTCAGGTTTACCAGAAGTTTGAGACCATGCTTATCAAT
AAGCTGAATTATCTTGTCTTCAAAGACATCTCAATCACAGAGAACGGCGGGCTGTTA
AAAGGATATCAGCTGACCTATATCCCCGACAAACTGAAAAATGTCGGGCACCAATG
CGGCTGTATTTTCTACGTGCCCGCTGCATACACATCTAAAATTGACCCAACGACTGG
ATTCGTAAATATTTTTAAGTTTAAGGATCTTACGGTAGATGCAAAGCGCGAATTTAT
CAAGAAATTTGATAGTATCCGTTACGACAGCGAGAAAAACTTATTTTGTTTTACGTT
CGATTATAACAACTTCATCACGCAAAATACCGTCATGTCAAAATCTTCCTGGTCAGT
CTATACGTATGGCGTCCGTATCAAGCGCCGCTTCGTCAACGGGCGTTTTTCAAACGA
GTCAGATACCATCGATATCACCAAAGATATGGAAAAAACATTGGAGATGACGGACA
TCAATTGGCGCGATGGTCATGACTTACGCCAGGACATTATTGACTACGAAATCGTAC
AACATATTTTTGAGATTTTCCGTCTGACCGTGCAAATGCGCAACTCATTATCCGAACT
TGAGGATCGTGATTACGACCGCTTGATCAGTCCTGTTCTGAACGAGAATAATATTTT
TTACGACAGTGCCAAGGCGGGAGACGCACTGCCCAAGGACGCTGACGCTAACGGAG
CTTATTGTATTGCGTTGAAGGGACTTTACGAAATCAAGCAAATCACTGAAAACTGGA
AGGAGGATGGTAAATTCTCACGCGACAAGTTGAAAATTTCGAACAAGGACTGGTTC
GATTTCATCCAAAACAAGCGTTATTTAAAACGTCCGGCAGCGACCAAAAAAGCCGG
CCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAAA
CGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 89
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGGACTA
ATAACTTCCAGAACTTCATCGGTATTTCATCATTACAAAAAACGCTTCGTAACGCCT
TGATCCCAACAGAAACGACCCAACAATTTATTGTAAAAAACGGCATCATCAAAGAA
GACGAACTGCGTGGCGAAAATCGCCAAATTTTGAAGGACATTATGGATGACTATTAT
CGTGGGTTTATCTCGGAGACATTATCCTCCATCGACGACATTGATTGGACGAGTCTT
TTTGAGAAAATGGAGATCCAGCTTAAAAATGGTGATAACAAGGATACATTGATCAA
GGAGCAAACCGAGTACCGCAAGGCCATCCATAAGAAGTTCGCAAATGACGACCGCT
TCAAAAATATGTTTAGTGCCAAATTGATCTCGGATATCCTTCCTGAGTTCGTAATTCA
CAACAATAATTATAGCGCATCCGAAAAGGAGGAAAAGACTCAAGTCATTAAGCTTT
TCAGTCGCTTTGCTACCTCGTTTAAGGACTATTTCAAGAACCGCGCGAACTGCTTCTC
AGCGGATGACATTTCTTCCTCGTCGTGTCACCGCATCGTGAATGATAATGCGGAGAT
CTTCTTTAGTAATGCCTTGGTATACCGCCGCATTGTTAAATCCCTGTCTAACGACGAT
ATCAATAAGATCTCAGGAGATATGAAGGATAGCCTTAAAGAAATGTCTCTGGAAGA
AATTTACTCCTATGAAAAGTACGGTGAGTTTATCACCCAAGAGGGGATTAGCTTTTA
TAACGATATCTGCGGGAAGGTGAATTCGTTTATGAACCTTTATTGTCAAAAGAATAA
GGAGAATAAGAACTTATATAAGCTTCAGAAACTGCATAAACAAATCTTATGCATTGC
CGATACTAGCTATGAAGTTCCGTATAAATTCGAGAGCGATGAAGAAGTTTATCAGA
GCGTCAATGGGTTCTTGGATAACATTTCATCAAAACACATCGTGGAACGTCTGCGTA
AGATTGGGGATAACTACAACGGATATAATCTTGACAAAATTTATATTGTATCTAAAT
TCTATGAGTCGGTGAGTCAAAAGACCTACCGTGATTGGGAAACAATCAATACCGCG
TTAGAAATCCACTATAACAACATTCTGCCAGGGAATGGTAAAAGTAAAGCGGACAA
AGTCAAGAAGGCTGTGAAGAACGATCTGCAAAAGAGTATTACAGAGATTAACGAAT
TAGTCTCCAATTATAAGTTATGCTCGGACGATAACATTAAGGCGGAGACGTATATTC
ATGAGATTTCGCATATTCTTAACAACTTCGAGGCACAAGAGCTTAAGTATAACCCAG
AGATTCACCTTGTCGAATCGGAGCTGAAGGCATCGGAATTAAAAAATGTCTTAGATG
TAATCATGAACGCGTTCCATTGGTGCAGTGTTTTCATGACTGAGGAGTTAGTTGACA
AGGACAATAACTTCTACGCAGAATTAGAAGAGATCTATGATGAGATTTATCCAGTG
ATTTCGCTGTATAATCTGGTACGTAATTACGTCACTCAAAAGCCCTACTCAACAAAA
AAAATTAAGCTGAACTTCGGAATTCCGACTCTGGCCGACGGGTGGTCCAAGTCAAA
GGAGTATTCTAATAATGCTATCATCCTGATGCGCGATAACTTATACTATTTGGGAAT
TTTCAATGCCAAAAATAAACCAGATAAAAAGATTATCGAAGGTAATACAAGCGAGA
ATAAGGGTGACTATAAGAAAATGATTTACAATCTTCTTCCAGGCCCTAACAAGATGA
TTCCCAAAGTTTTTTTGTCCAGTAAAACAGGGGTCGAAACTTACAAGCCCAGTGCCT
ATATCCTTGAAGGGTACAAGCAGAATAAGCACATCAAATCCTCGAAAGACTTTGAT
ATTACATTTTGTCATGACTTAATCGATTATTTTAAGAACTGTATCGCAATCCATCCAG
AATGGAAGAACTTCGGGTTTGATTTCTCTGATACTTCCACGTATGAGGATATTTCCG
GGTTCTACCGCGAAGTAGAGCTTCAGGGCTATAAAATTGACTGGACATATATTTCAG
AAAAAGACATCGATCTGTTACAAGAAAAAGGACAGTTGTATCTGTTTCAAATCTATA
ATAAGGATTTCTCCAAAAAGTCAACTGGAAATGATAACTTACATACAATGTATCTGA
AAAATCTTTTTAGTGAAGAGAATTTGAAGGATATCGTGCTGAAGTTAAATGGCGAA
GCAGAGATCTTCTTCCGCAAGTCCTCGATCAAGAATCCTATCATCCACAAGAAAGGT
AGTATTCTGGTTAACCGCACGTACGAGGCCGAGGAAAAAGACCAGTTCGGTAATAT
CCAGATTGTACGTAAGAATATTCCTGAAAATATTTACCAGGAATTATACAAGTATTT
TAACGACAAATCGGATAAGGAGCTTTCAGATGAGGCCGCAAAGTTGAAGAACGTCG
TAGGACACCATGAGGCCGCTACGAATATCGTCAAGGACTACCGCTATACGTATGAC
AAGTACTTCCTGCACATGCCTATTACTATCAATTTCAAAGCTAATAAAACAGGATTC
ATCAATGATCGTATCCTTCAGTACATTGCCAAAGAAAAAGATCTGCACGTAATCGGA
ATCGACCGTGGCGAACGTAATCTGATTTACGTATCAGTTATCGACACATGTGGTAAC
ATCGTGGAGCAGAAATCTTTTAACATTGTTAACGGCTATGATTATCAGATTAAGCTT
AAACAGCAGGAGGGGGCACGCCAAATCGCTCGTAAAGAATGGAAGGAGATTGGAA
AGATTAAAGAGATTAAAGAGGGGTACCTTTCGCTGGTTATTCACGAAATTTCCAAGA
TGGTGATTAAGTACAATGCAATCATCGCGATGGAAGATCTTAGTTACGGATTCAAAA
AGGGACGCTTCAAAGTTGAGCGTCAGGTCTACCAGAAATTTGAAACGATGCTGATT
AACAAATTGAATTACTTGGTATTCAAAGATATCTCAATTACTGAAAATGGTGGCTTA
TTAAAGGGTTACCAGCTTACCTATATCCCGGATAAGCTGAAGAACGTGGGCCATCAA
TGCGGCTGCATCTTTTACGTCCCTGCCGCATATACCTCTAAAATTGACCCCACCACCG
GATTCGTAAATATTTTTAAATTCAAGGACCTGACGGTGGACGCCAAGCGCGAATTCA
TCAAAAAATTCGACTCAATCCGCTATGATTCCGAAAAAAATCTTTTCTGCTTTACGTT
CGATTATAATAACTTCATTACCCAAAACACGGTGATGTCAAAATCGTCCTGGAGCGT
GTATACTTATGGAGTGCGTATCAAGCGCCGCTTTGTTAATGGGCGCTTCAGTAACGA
AAGCGATACCATCGACATTACCAAAGACATGGAGAAGACGCTTGAAATGACGGATA
TCAATTGGCGTGACGGACACGATCTTCGTCAGGATATCATCGACTACGAGATTGTGC
AACATATCTTTGAGATTTTCCGTTTAACTGTTCAAATGCGTAACTCCTTGTCCGAATT
GGAAGACCGTGATTACGACCGCTTGATTTCACCAGTGCTTAACGAGAATAACATCTT
CTACGACTCCGCCAAAGCAGGCGATGCCCTGCCAAAGGACGCTGATGCAAATGGTG
CATACTGTATCGCGTTGAAGGGCTTATACGAGATTAAGCAAATCACCGAAAATTGG
AAAGAGGATGGAAAGTTCAGTCGCGATAAGCTGAAGATCTCTAATAAAGATTGGTT
TGACTTTATCCAGAACAAACGTTATTTAAAACGTCCGGCAGCGACCAAAAAAGCCG
GCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAA
ACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 90
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGTACCA
ATAATTTCCAAAATTTCATCGGAATCTCATCCTTGCAAAAAACCTTGCGCAATGCTTT
GATCCCCACCGAAACCACGCAGCAGTTCATCGTGAAAAACGGCATTATCAAAGAGG
ATGAGTTGCGCGGGGAAAACCGTCAAATTCTTAAGGATATCATGGACGATTACTACC
GTGGGTTTATCAGTGAGACCCTGTCAAGCATTGACGACATTGACTGGACCAGCTTAT
TTGAGAAGATGGAGATTCAATTAAAGAACGGGGACAATAAGGACACGCTTATCAAA
GAGCAGACAGAATACCGTAAAGCGATTCATAAGAAATTTGCAAATGACGATCGCTT
CAAGAACATGTTTTCAGCAAAATTAATCAGCGACATCCTTCCCGAATTTGTGATTCA
TAATAACAACTATTCGGCTAGCGAAAAAGAGGAGAAAACTCAGGTTATTAAGCTTT
TCTCGCGTTTTGCCACTTCGTTCAAAGACTATTTTAAGAATCGCGCAAACTGCTTTTC
GGCTGATGATATTTCCAGTTCTAGCTGCCATCGTATCGTTAACGATAATGCTGAGAT
TTTCTTCTCTAATGCCCTGGTGTATCGTCGTATCGTTAAATCTTTGAGCAACGACGAT
ATTAATAAGATTTCAGGCGACATGAAGGATTCTTTAAAGGAGATGTCTTTAGAAGAG
ATTTATTCCTATGAGAAATATGGCGAGTTTATCACCCAAGAAGGAATTTCGTTCTAC
AACGACATCTGTGGCAAAGTGAACAGCTTCATGAATTTATACTGCCAAAAGAATAA
GGAGAATAAAAATTTATATAAACTGCAGAAACTGCATAAGCAAATTCTTTGCATTGC
AGACACCTCTTATGAAGTTCCTTATAAGTTTGAATCGGACGAGGAGGTATATCAGAG
TGTGAACGGGTTCCTGGACAATATTTCATCCAAGCATATTGTTGAACGTTTACGCAA
AATTGGAGACAATTACAATGGGTATAACCTTGACAAAATTTACATCGTGTCGAAGTT
TTACGAATCGGTAAGCCAGAAGACCTATCGTGACTGGGAAACTATCAATACCGCCTT
AGAAATTCATTACAACAATATTCTTCCTGGTAACGGCAAAAGCAAAGCCGATAAGG
TAAAGAAGGCTGTCAAGAACGACCTGCAAAAGTCTATCACAGAGATCAACGAGTTA
GTCTCTAACTACAAATTATGTTCCGACGACAATATTAAAGCCGAAACCTACATCCAT
GAGATCTCACACATTCTTAACAATTTTGAGGCCCAGGAGCTGAAATATAACCCAGAA
ATTCACCTTGTAGAGAGCGAATTAAAAGCCTCCGAGCTGAAGAACGTTTTGGATGTA
ATCATGAACGCATTTCATTGGTGCAGCGTATTTATGACAGAGGAGTTGGTCGACAAG
GACAATAACTTTTACGCCGAGCTTGAAGAAATCTACGATGAAATTTACCCGGTAATT
AGTTTATATAATTTAGTTCGCAACTACGTAACTCAGAAACCCTACAGTACCAAGAAG
ATTAAATTGAACTTTGGGATCCCGACACTTGCTGACGGTTGGAGTAAATCAAAAGAA
TACTCCAATAATGCAATTATCCTGATGCGCGACAATCTTTACTACTTGGGGATCTTTA
ACGCAAAGAACAAACCAGATAAGAAAATCATCGAGGGCAACACCAGCGAGAATAA
AGGCGATTACAAGAAAATGATCTATAATCTTTTGCCGGGACCGAACAAAATGATCC
CAAAGGTTTTCCTGTCGTCGAAAACGGGAGTCGAGACATATAAACCATCTGCGTACA
TCTTGGAAGGTTACAAACAGAATAAGCATATTAAGTCTAGTAAAGACTTCGACATCA
CCTTTTGTCATGACCTGATTGATTATTTCAAGAACTGTATTGCTATCCATCCAGAATG
GAAAAACTTCGGATTTGACTTCTCCGATACTAGCACCTACGAAGACATTTCGGGTTT
TTATCGCGAAGTAGAGCTTCAAGGGTACAAAATTGATTGGACATATATTAGCGAGA
AAGACATTGATTTGCTTCAAGAGAAGGGACAGTTATATTTATTCCAGATCTACAACA
AAGACTTCTCGAAGAAATCCACCGGTAATGATAATCTTCACACTATGTACCTGAAGA
ATTTATTTTCAGAGGAAAATCTGAAGGACATTGTACTTAAACTTAATGGAGAAGCCG
AAATCTTCTTCCGCAAGAGTTCCATTAAAAATCCGATTATTCATAAAAAGGGAAGTA
TCCTTGTGAACCGCACGTATGAGGCCGAAGAGAAGGATCAGTTTGGGAATATTCAA
ATTGTCCGCAAAAACATCCCCGAGAACATCTACCAGGAACTGTATAAATACTTTAAT
GATAAATCTGATAAAGAGTTATCAGACGAGGCTGCCAAACTGAAAAACGTAGTCGG
TCATCATGAGGCAGCGACCAATATTGTAAAGGACTACCGTTACACCTACGACAAGT
ATTTCCTTCACATGCCGATCACGATTAATTTTAAGGCTAACAAGACCGGCTTTATCA
ATGACCGCATCTTGCAGTACATCGCGAAAGAGAAAGATTTACACGTCATCGGAATT
GATCGTGGAGAGCGTAATCTTATCTACGTCAGCGTCATCGACACCTGTGGAAACATT
GTGGAACAAAAAAGTTTTAATATCGTAAACGGCTACGACTATCAAATTAAACTTAA
ACAGCAAGAGGGAGCTCGCCAGATCGCTCGCAAAGAGTGGAAAGAGATTGGGAAA
ATTAAAGAAATTAAAGAGGGTTACCTGTCGCTGGTAATTCACGAAATCTCGAAAAT
GGTCATCAAATATAATGCAATTATCGCTATGGAGGATCTGTCCTACGGGTTCAAGAA
GGGACGTTTTAAAGTAGAGCGCCAGGTGTATCAAAAATTCGAAACCATGTTGATCA
ATAAGCTTAACTATTTGGTCTTCAAAGATATTTCGATTACGGAGAACGGAGGTTTGT
TGAAAGGATATCAGCTGACGTATATCCCAGACAAGTTGAAAAACGTGGGGCATCAA
TGTGGATGTATTTTCTATGTGCCCGCGGCCTACACGAGTAAGATCGATCCTACCACT
GGTTTCGTCAACATTTTCAAATTTAAAGATCTTACCGTGGATGCGAAGCGCGAATTT
ATTAAGAAATTTGATAGCATTCGCTATGATTCCGAAAAGAACCTGTTCTGTTTTACG
TTCGACTATAACAATTTCATTACCCAAAACACGGTGATGAGCAAATCCTCTTGGTCA
GTTTATACATACGGTGTACGTATCAAACGCCGTTTCGTTAACGGACGCTTTTCCAAT
GAGTCTGATACAATCGATATCACGAAAGATATGGAAAAAACATTAGAGATGACTGA
TATCAACTGGCGTGACGGGCACGACCTGCGTCAAGACATTATTGACTACGAGATTGT
GCAGCATATCTTCGAAATCTTTCGCTTAACTGTGCAAATGCGTAACTCGTTATCCGA
GTTAGAAGACCGTGACTACGATCGCCTGATTTCACCCGTCTTGAACGAAAATAACAT
CTTCTACGATTCCGCGAAGGCTGGGGACGCATTGCCCAAGGACGCAGACGCGAATG
GAGCGTACTGTATTGCGCTTAAAGGATTATATGAAATCAAGCAGATCACCGAAAATT
GGAAGGAGGACGGGAAGTTCTCACGCGACAAACTGAAGATTTCAAATAAGGACTGG
TTCGATTTCATTCAGAATAAGCGTTACCTGAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 91
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAATGGTACGAA
CAACTTTCAGAACTTCATCGGCATCTCCAGCCTTCAAAAGACTTTACGCAACGCATT
GATTCCCACGGAGACTACGCAACAGTTTATCGTAAAAAATGGTATTATCAAAGAAG
ATGAATTACGCGGGGAGAATCGCCAGATTCTTAAGGACATTATGGACGATTATTACC
GTGGATTCATCAGTGAGACACTGAGCTCCATTGATGACATCGACTGGACGTCATTGT
TTGAAAAGATGGAAATCCAGTTGAAAAATGGCGATAACAAAGATACATTGATTAAA
GAGCAGACAGAGTACCGCAAAGCAATTCACAAGAAATTCGCCAATGATGATCGTTT
TAAGAACATGTTTAGTGCCAAGCTTATTTCGGATATCTTACCCGAATTCGTGATTCAC
AACAACAATTATTCGGCAAGTGAGAAAGAGGAAAAGACCCAGGTTATCAAATTGTT
TTCGCGCTTCGCCACTTCGTTCAAAGATTATTTCAAGAACCGTGCAAACTGTTTCTCC
GCTGACGACATCAGTTCCAGCTCATGCCACCGTATTGTAAATGACAATGCGGAGATC
TTTTTCAGTAATGCCTTAGTATATCGTCGCATTGTAAAGAGCTTATCTAATGATGACA
TTAACAAGATCTCGGGTGATATGAAGGACTCACTTAAGGAGATGAGTCTGGAAGAG
ATCTACTCCTACGAAAAATACGGGGAATTCATCACCCAGGAGGGAATTTCATTCTAC
AACGATATCTGCGGCAAAGTTAACTCCTTTATGAATCTGTACTGTCAAAAGAACAAG
GAGAATAAAAACCTGTATAAATTGCAGAAACTTCATAAACAAATTTTGTGTATCGCA
GACACGAGTTATGAAGTACCTTATAAATTCGAATCCGACGAAGAGGTATATCAGTCC
GTAAATGGGTTCCTGGACAATATCAGTAGTAAGCACATTGTGGAACGCTTACGCAA
AATTGGAGACAATTACAACGGGTATAACCTGGACAAAATCTACATCGTATCCAAATT
TTATGAAAGCGTGTCTCAAAAAACTTATCGTGATTGGGAAACAATCAACACGGCTCT
TGAGATCCATTACAATAACATCTTGCCGGGTAACGGCAAATCGAAGGCAGACAAAG
TTAAAAAAGCAGTTAAGAACGACTTACAGAAAAGCATTACGGAGATTAACGAGTTA
GTAAGTAATTACAAATTATGCTCCGACGATAATATCAAAGCTGAAACCTACATCCAT
GAAATTAGCCACATTTTGAACAATTTCGAAGCGCAGGAGCTGAAATATAACCCTGA
AATCCATCTGGTAGAGTCTGAGTTGAAGGCGTCAGAACTGAAAAACGTTCTTGACGT
CATCATGAATGCCTTTCACTGGTGTAGTGTTTTTATGACTGAGGAGCTTGTAGATAA
GGACAACAACTTCTATGCTGAACTTGAAGAGATCTACGATGAAATCTACCCCGTAAT
CAGTCTGTATAATTTAGTTCGTAACTACGTCACGCAGAAACCCTATTCGACTAAGAA
AATTAAGCTGAACTTTGGGATCCCTACTTTGGCAGACGGGTGGAGCAAGAGTAAAG
AATACAGTAATAATGCAATTATCTTGATGCGCGATAACTTATATTACTTAGGTATTTT
CAATGCTAAGAACAAACCTGATAAGAAGATTATCGAAGGAAATACGAGTGAGAATA
AGGGAGACTACAAAAAGATGATTTACAACTTGCTGCCAGGGCCTAATAAGATGATT
CCAAAAGTTTTTCTGTCGAGCAAGACAGGGGTTGAAACTTATAAGCCATCCGCTTAT
ATCCTTGAGGGGTACAAGCAGAATAAGCATATCAAGTCCTCCAAAGATTTTGATATT
ACATTTTGCCACGACTTAATTGATTACTTCAAGAACTGCATCGCAATCCATCCCGAA
TGGAAGAATTTCGGCTTCGATTTCTCAGATACGTCCACGTATGAGGATATCTCAGGC
TTTTACCGCGAAGTTGAGCTGCAAGGTTATAAAATTGATTGGACATACATCTCCGAA
AAAGACATTGATCTTTTACAGGAAAAGGGCCAATTATACTTATTTCAAATCTATAAC
AAAGATTTTAGCAAGAAGTCCACAGGTAATGATAACCTGCATACGATGTATTTGAA
AAATCTTTTCAGTGAAGAGAATTTGAAGGATATCGTCCTGAAGCTGAACGGTGAGG
CTGAGATCTTCTTCCGCAAATCGTCTATCAAAAACCCCATCATTCACAAAAAGGGAA
GTATCTTAGTAAACCGCACTTATGAAGCGGAGGAAAAGGATCAGTTCGGGAACATC
CAGATCGTGCGCAAGAACATTCCAGAAAACATCTATCAGGAACTTTACAAATATTTC
AATGACAAGTCTGATAAAGAATTATCAGACGAGGCGGCGAAACTTAAAAATGTTGT
TGGACACCACGAAGCAGCGACGAATATTGTAAAGGATTATCGCTACACATACGATA
AATACTTTTTGCACATGCCAATCACCATTAACTTTAAGGCGAACAAGACAGGTTTCA
TTAACGACCGTATTCTGCAATATATCGCAAAGGAAAAAGACCTGCACGTTATTGGGA
TCGATCGTGGCGAACGCAATTTGATCTACGTAAGCGTTATCGACACTTGCGGAAATA
TCGTTGAACAAAAAAGCTTTAATATCGTCAATGGATACGATTACCAAATCAAGCTGA
AACAACAAGAAGGGGCACGTCAGATCGCTCGTAAAGAATGGAAAGAGATTGGTAA
GATCAAAGAGATTAAAGAAGGGTATCTTTCTTTAGTAATTCACGAGATTTCGAAAAT
GGTTATTAAATACAATGCGATTATTGCTATGGAAGACTTAAGCTACGGCTTTAAGAA
AGGTCGCTTCAAAGTGGAGCGCCAAGTGTATCAGAAGTTTGAAACGATGTTGATTA
ACAAATTAAATTACCTGGTCTTTAAGGACATCAGTATCACAGAAAATGGGGGGTTGC
TTAAAGGGTACCAGCTTACATACATCCCTGATAAACTGAAAAATGTCGGTCATCAGT
GCGGATGTATCTTCTATGTACCAGCAGCCTATACCAGTAAGATTGACCCTACTACTG
GCTTTGTGAATATTTTTAAATTCAAGGATTTAACCGTGGACGCCAAGCGTGAATTTA
TTAAAAAATTTGATTCGATTCGCTACGACAGTGAGAAAAACCTTTTCTGCTTTACCTT
TGACTACAACAATTTTATTACCCAGAACACCGTAATGTCAAAGAGTTCGTGGTCTGT
ATATACCTACGGTGTTCGCATCAAGCGCCGCTTCGTAAACGGGCGTTTCAGTAACGA
ATCTGACACCATCGACATCACTAAAGATATGGAGAAGACATTGGAAATGACGGACA
TTAATTGGCGTGATGGCCATGACTTACGTCAGGACATTATTGATTACGAAATTGTGC
AGCATATCTTCGAGATTTTCCGTTTGACAGTTCAGATGCGCAACTCACTGAGTGAGT
TAGAAGATCGCGATTACGACCGTCTGATCTCACCGGTCCTTAATGAAAACAACATTT
TCTACGACTCAGCAAAGGCGGGTGATGCCCTGCCAAAGGATGCGGACGCTAATGGC
GCCTACTGCATCGCCCTGAAAGGATTGTATGAAATTAAGCAGATTACAGAAAATTG
GAAGGAAGATGGTAAATTTAGCCGTGATAAATTAAAAATCTCGAACAAGGATTGGT
TCGATTTTATTCAGAACAAACGTTATTTGAAACGTCCGGCAGCGACCAAAAAAGCCG
GCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAA
ACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 92
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAATGGAACAA
ATAATTTTCAAAATTTTATCGGCATCTCAAGTCTTCAAAAAACCCTTCGCAATGCCCT
GATTCCAACTGAAACAACCCAGCAATTTATCGTCAAGAACGGCATCATTAAGGAAG
ACGAGTTACGCGGGGAGAACCGTCAAATCCTGAAAGATATCATGGATGACTACTAT
CGTGGGTTCATTTCGGAAACCTTGTCTTCAATCGACGACATTGACTGGACGAGTCTT
TTCGAGAAAATGGAAATTCAGCTTAAAAATGGAGACAACAAGGATACTCTGATTAA
GGAACAGACAGAATATCGCAAAGCTATCCACAAAAAGTTCGCTAATGATGATCGTT
TCAAAAATATGTTTTCTGCTAAATTGATTTCCGATATCTTGCCTGAATTTGTAATCCA
CAACAACAATTATTCTGCTTCCGAGAAGGAAGAGAAGACCCAGGTCATTAAATTATT
CAGCCGCTTTGCAACCAGCTTTAAAGACTACTTTAAGAATCGCGCTAACTGCTTTTC
GGCGGATGACATCTCATCATCATCATGCCACCGCATTGTGAACGACAATGCGGAGAT
CTTCTTTTCGAATGCGTTAGTTTATCGTCGCATTGTCAAAAGTCTTAGCAATGATGAC
ATCAACAAGATCTCAGGAGACATGAAAGATTCCTTAAAGGAGATGTCTCTTGAGGA
AATCTATTCGTATGAGAAATACGGCGAGTTCATTACCCAGGAAGGTATTAGTTTCTA
CAATGATATCTGCGGCAAAGTAAATTCTTTTATGAATCTGTATTGCCAAAAAAACAA
AGAAAACAAGAATCTTTATAAGTTACAAAAGTTACATAAGCAAATTCTGTGCATCGC
TGATACATCTTATGAGGTACCCTACAAATTTGAAAGTGATGAGGAGGTCTATCAGAG
TGTCAACGGCTTCTTAGACAACATCTCTTCCAAACATATCGTGGAACGCCTGCGTAA
AATCGGAGATAACTACAACGGATATAACTTAGATAAAATCTACATCGTGTCCAAGTT
TTATGAAAGTGTGAGCCAAAAAACATATCGTGACTGGGAAACCATTAACACCGCAT
TGGAAATTCACTATAACAACATTTTGCCAGGCAACGGGAAAAGTAAGGCGGACAAA
GTTAAGAAAGCAGTTAAAAATGACCTGCAAAAAAGCATCACTGAAATTAACGAATT
GGTATCGAATTACAAATTATGTAGCGACGATAATATCAAAGCAGAAACTTACATTCA
CGAGATTAGTCACATTTTAAATAACTTCGAGGCCCAGGAATTGAAATACAATCCCGA
AATTCATTTGGTTGAATCAGAACTGAAAGCATCAGAGTTGAAAAATGTGTTAGATGT
CATTATGAATGCGTTTCATTGGTGCTCTGTGTTCATGACCGAGGAACTGGTTGATAA
AGATAACAACTTTTACGCTGAATTGGAGGAGATTTACGATGAGATTTACCCGGTCAT
TTCGCTTTATAACTTAGTGCGCAATTATGTGACGCAGAAACCATATTCCACGAAGAA
AATCAAACTTAATTTTGGCATCCCTACTCTGGCTGATGGTTGGTCGAAATCGAAAGA
GTACAGCAACAACGCGATCATTCTTATGCGTGACAATCTTTACTATTTGGGCATTTTT
AATGCCAAGAATAAGCCAGATAAGAAAATCATTGAGGGGAATACTTCCGAGAATAA
GGGGGATTACAAAAAGATGATCTATAACTTGCTGCCCGGCCCCAACAAAATGATTC
CTAAGGTTTTCTTGTCAAGCAAGACGGGCGTCGAAACATATAAGCCGTCAGCTTATA
TTCTGGAAGGCTATAAACAGAATAAGCACATCAAGTCTTCCAAGGACTTTGACATCA
CTTTTTGCCACGATTTGATCGACTACTTTAAGAACTGTATTGCGATTCATCCGGAATG
GAAGAACTTCGGTTTCGACTTTTCCGATACCTCAACATACGAGGATATCAGCGGCTT
CTACCGTGAAGTCGAGCTTCAAGGCTACAAGATCGATTGGACATATATTTCAGAGAA
GGACATTGATTTGTTACAAGAGAAAGGTCAACTTTACTTATTTCAGATCTATAACAA
AGACTTTTCGAAGAAATCGACAGGAAACGATAACTTACACACTATGTATTTAAAAA
ATCTGTTTTCGGAGGAAAACCTGAAAGATATTGTGCTGAAACTTAACGGCGAGGCA
GAGATCTTTTTCCGTAAAAGCTCAATCAAGAATCCTATCATCCATAAAAAAGGTAGT
ATTCTTGTCAACCGCACATATGAAGCGGAGGAGAAGGACCAATTCGGAAACATCCA
AATTGTCCGTAAGAATATTCCGGAGAACATTTACCAAGAGTTGTATAAATACTTTAA
CGATAAGTCAGATAAGGAACTTAGCGATGAGGCGGCGAAGCTTAAAAACGTAGTTG
GGCATCATGAAGCTGCTACCAACATTGTAAAAGATTACCGTTACACCTATGACAAGT
ATTTCTTGCACATGCCCATTACGATCAATTTCAAAGCAAATAAGACAGGCTTTATCA
ATGATCGCATCCTGCAGTACATTGCTAAAGAGAAGGATTTGCATGTTATCGGTATTG
ATCGCGGAGAGCGCAATTTGATCTACGTCTCCGTAATCGACACTTGCGGTAACATTG
TTGAGCAGAAGTCGTTCAACATCGTTAATGGTTATGATTACCAAATCAAGCTGAAGC
AGCAAGAGGGTGCCCGCCAGATCGCGCGTAAGGAATGGAAAGAAATCGGGAAAAT
TAAAGAGATCAAAGAAGGCTATTTGTCTCTGGTAATTCACGAAATCAGCAAGATGG
TGATCAAGTATAACGCGATCATTGCGATGGAGGATCTTTCTTATGGCTTCAAGAAAG
GGCGCTTTAAAGTCGAACGCCAGGTCTACCAGAAATTTGAGACAATGCTTATCAACA
AGCTTAACTATCTTGTATTTAAGGATATTTCCATCACTGAGAACGGAGGACTTTTAA
AGGGGTACCAACTGACGTACATTCCTGATAAGCTGAAGAACGTTGGTCATCAATGC
GGATGCATCTTCTATGTGCCAGCGGCTTACACCTCCAAAATCGATCCCACTACAGGC
TTTGTCAATATCTTCAAATTCAAGGATTTGACCGTTGACGCGAAGCGCGAGTTTATC
AAGAAGTTTGATAGCATTCGCTACGACAGCGAAAAAAATTTATTTTGTTTTACTTTC
GACTACAATAACTTTATTACTCAGAACACTGTCATGTCAAAGAGTTCGTGGAGTGTC
TACACGTACGGAGTACGTATTAAGCGCCGTTTCGTCAACGGACGCTTCTCAAACGAA
AGCGACACGATCGACATCACCAAAGACATGGAAAAAACTCTTGAGATGACGGATAT
CAATTGGCGCGACGGCCATGACCTGCGTCAGGATATCATTGATTACGAGATCGTTCA
GCACATCTTCGAAATCTTCCGCCTTACCGTCCAGATGCGCAACAGTTTAAGCGAGCT
TGAAGACCGCGACTACGATCGTTTGATTAGCCCCGTTCTGAACGAGAATAATATTTT
CTACGACAGCGCAAAGGCCGGTGATGCTTTGCCAAAGGACGCAGACGCGAATGGAG
CCTACTGCATCGCCCTGAAGGGCTTATATGAGATTAAGCAAATTACCGAAAATTGGA
AGGAAGATGGTAAGTTCTCCCGTGATAAGCTTAAAATTAGCAATAAGGATTGGTTCG
ACTTCATCCAGAACAAACGTTACCTGAAACGTCCGGCAGCGACCAAAAAAGCCGGC
CAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAAAC
GTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 93
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGAACAA
ACAATTTCCAAAACTTCATCGGTATCTCTTCGTTGCAGAAGACTCTGCGTAATGCTTT
GATCCCGACGGAGACAACCCAACAATTTATCGTCAAAAACGGTATTATTAAGGAGG
ACGAGTTACGTGGAGAAAATCGTCAAATCCTTAAGGACATCATGGACGATTATTATC
GCGGGTTTATTTCTGAAACCCTGAGCAGTATCGATGATATCGACTGGACCTCACTTT
TTGAGAAAATGGAGATCCAGTTGAAGAACGGTGATAACAAAGACACTCTGATCAAA
GAGCAAACTGAATACCGCAAGGCAATTCACAAAAAGTTCGCCAACGACGACCGTTT
CAAGAATATGTTCTCAGCTAAGTTAATCAGCGACATTTTGCCAGAGTTCGTTATCCA
CAACAATAATTATAGTGCTTCAGAGAAGGAGGAAAAAACCCAAGTGATTAAACTTT
TTTCGCGCTTTGCAACCTCATTCAAGGACTACTTCAAGAATCGCGCGAATTGCTTCA
GTGCGGACGACATTTCTTCTTCAAGTTGCCATCGTATCGTTAACGATAACGCGGAAA
TTTTCTTCTCTAATGCTTTGGTGTATCGCCGCATTGTAAAATCGCTTAGTAACGATGA
CATTAATAAGATCTCAGGTGATATGAAAGATTCATTGAAGGAAATGAGCTTGGAAG
AGATTTACAGTTACGAAAAATATGGAGAATTTATTACTCAGGAAGGCATCTCATTCT
ATAACGATATCTGCGGGAAGGTAAATTCGTTTATGAACTTATATTGCCAGAAAAATA
AAGAGAATAAAAATTTGTATAAGCTTCAGAAGTTGCACAAACAGATCCTGTGCATT
GCAGACACCTCGTATGAGGTTCCGTATAAATTTGAGTCCGATGAAGAAGTGTATCAG
TCTGTGAATGGTTTCTTAGATAATATCTCTTCCAAGCATATTGTCGAACGCCTGCGCA
AAATTGGTGATAACTATAACGGATACAATCTGGATAAAATTTACATCGTTTCTAAAT
TTTACGAGTCAGTCTCGCAGAAGACCTACCGCGACTGGGAAACAATTAACACGGCA
TTGGAGATTCACTACAATAATATCTTGCCTGGTAACGGTAAGTCTAAGGCAGATAAG
GTAAAAAAAGCTGTGAAAAACGACCTTCAGAAAAGCATCACGGAGATTAATGAGCT
GGTGAGTAATTACAAATTATGTTCAGACGATAATATTAAAGCTGAAACGTATATCCA
TGAAATCTCGCATATCTTGAACAACTTCGAGGCCCAAGAACTTAAATATAACCCCGA
AATCCATTTAGTCGAGTCTGAATTGAAAGCGTCGGAATTAAAAAACGTCTTAGACGT
CATTATGAACGCGTTTCACTGGTGTTCAGTTTTCATGACCGAAGAGCTGGTCGACAA
AGACAACAACTTCTATGCGGAATTGGAGGAAATCTATGATGAAATCTACCCTGTTAT
TTCACTGTATAACCTTGTGCGCAACTATGTCACTCAGAAGCCGTATTCGACCAAAAA
AATTAAATTGAATTTCGGTATCCCTACTCTTGCAGACGGATGGAGTAAAAGCAAGGA
ATACAGTAATAACGCCATTATTCTTATGCGCGACAATTTATACTACCTGGGCATCTTT
AACGCAAAGAATAAGCCGGATAAGAAGATTATTGAGGGTAACACCAGTGAGAACA
AGGGCGACTATAAGAAGATGATCTATAACTTATTGCCAGGTCCAAATAAAATGATC
CCAAAAGTATTCTTATCATCAAAGACGGGAGTTGAAACCTATAAGCCTAGTGCCTAT
ATTCTTGAGGGATATAAACAGAACAAGCACATTAAGTCGTCTAAGGATTTTGACATT
ACGTTCTGCCATGACTTAATCGACTATTTTAAAAACTGTATTGCGATTCACCCCGAAT
GGAAGAATTTTGGATTCGATTTTTCGGATACCTCGACCTATGAAGATATTTCGGGAT
TTTATCGTGAAGTGGAGTTGCAAGGCTATAAAATCGATTGGACCTATATCTCAGAAA
AAGACATTGATTTATTACAGGAAAAGGGACAACTGTACCTTTTCCAAATTTATAACA
AGGACTTTTCTAAAAAGTCCACAGGAAATGATAACCTTCACACCATGTACCTGAAGA
ACCTTTTCTCAGAGGAAAACCTGAAGGACATTGTCCTTAAGTTAAATGGAGAAGCG
GAGATCTTTTTCCGTAAATCTAGTATCAAGAATCCGATTATCCATAAAAAAGGTTCG
ATTTTGGTAAATCGCACCTATGAAGCGGAAGAGAAAGATCAATTTGGTAACATCCA
GATCGTGCGCAAGAATATCCCGGAGAACATTTACCAAGAGCTGTATAAGTACTTCA
ATGATAAGTCTGATAAGGAACTGTCAGATGAAGCTGCGAAATTGAAGAACGTGGTT
GGGCATCATGAAGCCGCTACCAATATCGTCAAGGATTACCGTTATACCTATGACAAA
TATTTCTTACACATGCCGATTACGATCAATTTTAAGGCAAACAAGACAGGATTCATC
AACGACCGTATCTTGCAGTATATTGCCAAAGAGAAGGATCTGCATGTGATCGGTATT
GACCGCGGGGAGCGCAATTTAATCTATGTATCGGTGATCGATACTTGTGGTAACATC
GTAGAACAAAAGAGCTTTAACATCGTGAATGGTTACGACTATCAGATCAAGCTGAA
ACAACAGGAAGGAGCCCGCCAGATCGCTCGCAAGGAATGGAAAGAAATCGGGAAA
ATTAAGGAAATCAAGGAAGGCTACCTTTCATTGGTCATTCACGAAATTTCGAAAATG
GTAATTAAGTACAACGCGATCATCGCCATGGAGGACCTTTCGTACGGATTTAAGAAG
GGTCGTTTCAAAGTTGAGCGCCAGGTATACCAAAAATTCGAGACTATGCTTATCAAC
AAACTTAACTACTTGGTCTTTAAGGACATTTCTATTACCGAAAACGGCGGCTTACTT
AAAGGCTATCAATTGACATATATTCCCGACAAACTGAAGAATGTTGGACATCAATGC
GGGTGTATTTTCTATGTGCCGGCAGCTTACACTAGTAAGATCGACCCTACAACCGGG
TTCGTAAACATTTTTAAATTCAAAGACTTAACAGTCGATGCGAAGCGTGAATTTATT
AAGAAGTTTGATAGTATCCGCTATGACAGTGAAAAGAACTTGTTTTGCTTTACGTTC
GACTACAATAACTTTATTACACAGAACACGGTCATGTCTAAATCATCATGGTCGGTT
TACACATATGGGGTGCGCATCAAGCGTCGCTTTGTAAATGGCCGTTTTAGTAATGAG
AGCGACACAATCGACATCACAAAGGATATGGAGAAAACTCTTGAGATGACAGACAT
CAATTGGCGTGACGGTCATGACTTACGCCAAGATATCATCGACTACGAAATCGTACA
GCATATTTTTGAGATTTTTCGTCTTACTGTGCAAATGCGTAATTCTTTATCCGAACTG
GAAGATCGTGATTACGACCGCTTGATTAGTCCCGTCTTAAATGAGAACAATATTTTC
TATGATTCTGCGAAAGCCGGAGATGCACTGCCCAAAGACGCTGATGCCAATGGCGC
GTATTGCATTGCATTAAAAGGATTATATGAGATTAAACAGATTACCGAAAATTGGAA
AGAGGACGGTAAATTCTCACGCGATAAATTGAAGATTTCTAACAAGGACTGGTTCG
ACTTTATCCAAAATAAACGTTATCTTAAACGTCCGGCAGCGACCAAAAAAGCCGGC
CAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAAAC
GTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 94
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGTACCAA
CAACTTTCAGAATTTCATTGGCATTAGCTCGCTTCAAAAAACTTTACGCAATGCTCTT
ATTCCGACTGAGACGACACAACAGTTTATCGTTAAGAATGGCATCATCAAAGAAGA
TGAATTACGCGGAGAAAACCGCCAGATCCTGAAAGACATTATGGACGATTATTACC
GTGGGTTCATCTCCGAGACGTTGTCATCGATCGATGACATCGACTGGACGTCACTTT
TTGAAAAAATGGAGATCCAGTTAAAGAACGGTGACAATAAGGATACATTGATCAAA
GAACAGACCGAGTACCGTAAAGCGATTCATAAAAAGTTTGCGAACGATGATCGCTT
CAAGAATATGTTTTCTGCGAAATTAATTTCCGACATTTTACCTGAATTTGTTATTCAT
AATAACAACTACTCGGCGTCTGAGAAAGAGGAGAAAACCCAAGTGATTAAACTTTT
TTCACGTTTCGCAACGTCGTTCAAAGACTATTTTAAAAATCGTGCTAATTGCTTTAGC
GCGGATGACATCAGCTCTAGTTCATGTCATCGCATTGTCAACGATAATGCTGAGATC
TTTTTCAGTAATGCGTTAGTGTACCGTCGTATTGTGAAGTCCTTATCTAATGATGATA
TCAATAAGATCAGCGGGGATATGAAGGACTCACTTAAGGAGATGAGCTTGGAGGAA
ATCTATTCCTATGAGAAGTATGGTGAGTTTATTACGCAAGAAGGAATTAGCTTTTAC
AACGATATCTGTGGAAAGGTGAATTCGTTTATGAATTTGTATTGCCAGAAAAATAAG
GAGAACAAGAACCTTTATAAATTGCAAAAGTTACACAAGCAAATCCTGTGCATTGC
AGATACTTCCTACGAGGTGCCTTACAAGTTTGAATCCGACGAAGAGGTCTACCAATC
TGTAAACGGTTTCTTAGATAATATTAGTTCCAAGCATATTGTGGAGCGCCTTCGTAA
AATTGGCGATAATTACAACGGTTACAATTTAGACAAAATTTACATTGTCAGTAAATT
CTACGAGTCCGTATCTCAAAAGACGTATCGTGATTGGGAGACTATCAATACGGCCCT
GGAGATCCACTACAACAATATCTTGCCCGGTAATGGTAAGTCGAAGGCCGATAAAG
TTAAGAAAGCGGTGAAAAATGACTTACAGAAGTCAATCACCGAAATTAACGAATTG
GTGTCCAATTATAAATTGTGTTCAGATGATAATATCAAAGCCGAGACCTACATTCAT
GAGATTTCCCATATCTTAAATAATTTCGAGGCGCAAGAGCTTAAGTATAACCCAGAA
ATCCACCTGGTAGAATCTGAGTTGAAGGCGTCAGAGTTAAAAAATGTTTTAGATGTC
ATTATGAACGCGTTTCACTGGTGCTCCGTATTTATGACGGAGGAATTAGTAGATAAA
GACAACAATTTCTATGCCGAACTTGAGGAAATCTATGATGAGATCTATCCCGTCATT
AGCCTGTATAACTTGGTCCGCAACTATGTTACCCAAAAACCGTACAGTACCAAGAAG
ATTAAGCTGAATTTCGGCATTCCTACACTGGCTGATGGTTGGAGTAAATCGAAGGAA
TATTCGAATAACGCGATTATCTTGATGCGCGACAACTTATACTATTTGGGGATCTTTA
ACGCCAAAAACAAACCGGATAAGAAGATTATTGAGGGAAACACATCAGAGAACAA
AGGCGACTACAAAAAAATGATTTACAACTTGTTACCGGGGCCTAACAAAATGATCC
CGAAGGTGTTCTTATCCAGTAAAACAGGCGTTGAGACCTACAAACCTTCCGCATACA
TCCTGGAAGGGTATAAGCAGAACAAGCACATTAAGTCCAGCAAGGATTTCGATATT
ACCTTCTGTCATGATTTAATTGACTATTTCAAGAACTGTATTGCAATCCACCCCGAGT
GGAAGAACTTCGGATTCGACTTCTCAGATACGAGCACATATGAGGACATCTCGGGG
TTCTATCGTGAAGTAGAACTGCAGGGATATAAAATTGATTGGACATATATTTCCGAA
AAAGACATCGACCTTTTACAAGAGAAGGGTCAACTTTACTTGTTCCAAATTTACAAT
AAAGACTTCTCAAAAAAAAGCACGGGTAACGATAATTTACACACTATGTATTTAAA
GAACCTTTTCTCGGAAGAGAATTTAAAGGATATCGTATTGAAGTTGAATGGAGAAG
CGGAGATCTTCTTCCGTAAGTCCAGTATTAAAAACCCTATTATTCACAAGAAGGGAT
CGATTTTAGTTAACCGCACATACGAGGCCGAAGAGAAGGACCAATTTGGGAACATT
CAAATTGTCCGCAAAAACATCCCTGAGAACATTTATCAAGAGCTTTATAAGTACTTT
AACGATAAGTCCGATAAGGAATTGTCAGATGAGGCGGCAAAGTTGAAGAATGTCGT
GGGGCATCATGAAGCTGCCACCAACATTGTGAAGGACTACCGCTACACTTACGACA
AATACTTCCTGCACATGCCCATTACGATCAATTTTAAGGCCAATAAGACAGGCTTTA
TTAACGACCGTATTCTTCAATATATCGCTAAGGAGAAGGACCTTCATGTGATTGGGA
TCGACCGCGGAGAACGTAATTTAATTTATGTGTCCGTCATCGATACGTGTGGAAATA
TCGTGGAACAGAAATCATTCAATATCGTGAATGGCTATGATTACCAGATCAAATTAA
AACAGCAGGAGGGCGCTCGCCAAATTGCGCGTAAGGAATGGAAAGAGATCGGAAA
AATCAAAGAAATCAAAGAAGGATATTTGTCATTGGTGATCCATGAGATTTCAAAAA
TGGTAATTAAATATAATGCAATTATCGCAATGGAAGACCTGTCCTATGGTTTTAAGA
AGGGTCGTTTCAAGGTAGAACGCCAAGTGTATCAAAAGTTCGAGACGATGCTGATC
AATAAGCTGAATTATCTTGTGTTTAAGGACATTAGCATCACGGAAAATGGAGGGCTG
TTGAAAGGCTATCAACTGACGTATATCCCTGACAAGCTGAAAAATGTTGGCCATCAG
TGCGGGTGCATTTTCTACGTCCCCGCGGCGTATACAAGCAAGATCGATCCTACTACG
GGATTCGTAAATATTTTTAAATTCAAAGACTTAACCGTGGACGCCAAGCGCGAATTC
ATTAAGAAGTTTGATAGCATTCGCTACGATTCAGAAAAAAATCTTTTCTGTTTTACGT
TCGATTACAACAATTTTATCACCCAGAACACAGTGATGAGCAAGTCATCCTGGTCTG
TCTATACCTACGGTGTCCGTATCAAACGCCGCTTCGTCAACGGACGCTTCTCTAATG
AATCTGATACCATTGACATCACCAAGGACATGGAAAAGACACTTGAGATGACAGAT
ATTAACTGGCGTGACGGACATGACCTGCGTCAGGACATCATCGATTATGAGATTGTT
CAGCATATCTTCGAGATCTTCCGCCTGACAGTACAAATGCGCAATTCACTGTCAGAA
CTTGAAGACCGCGACTATGACCGCCTGATCTCTCCAGTATTAAATGAGAACAATATC
TTTTATGACAGTGCTAAGGCCGGCGATGCCCTTCCGAAAGATGCTGATGCTAACGGA
GCTTATTGTATTGCATTAAAGGGTCTTTATGAGATCAAGCAAATTACCGAGAATTGG
AAGGAGGATGGCAAATTCTCGCGCGACAAACTGAAAATCAGTAACAAGGACTGGTT
CGATTTTATTCAGAATAAACGTTACCTGAAACGTCCGGCAGCGACCAAAAAAGCCG
GCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGAA
ACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 95
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGAACGA
ACAACTTCCAGAACTTCATCGGCATCAGTTCTTTACAAAAAACCCTGCGTAACGCCC
TTATTCCGACTGAGACAACACAACAGTTCATCGTTAAAAACGGAATTATCAAAGAG
GACGAGTTGCGCGGCGAGAATCGCCAAATTTTGAAAGATATTATGGACGACTATTAT
CGTGGTTTTATTTCAGAAACACTGAGTTCGATTGACGATATCGATTGGACGAGCCTG
TTTGAGAAAATGGAAATCCAGTTGAAAAATGGCGATAATAAAGACACTTTAATCAA
AGAACAAACCGAGTATCGTAAAGCGATCCATAAAAAGTTCGCTAATGACGATCGTT
TTAAGAATATGTTCAGTGCGAAACTGATTTCAGACATTTTGCCCGAGTTCGTGATCC
ATAATAACAACTATTCCGCCTCGGAAAAGGAAGAAAAAACCCAGGTGATTAAGCTG
TTCAGTCGCTTCGCAACATCTTTCAAGGATTATTTCAAGAATCGCGCGAATTGCTTCA
GTGCGGACGATATTTCTAGTTCAAGCTGCCATCGTATCGTTAATGATAACGCGGAGA
TTTTTTTTAGCAATGCTCTGGTGTACCGCCGCATTGTTAAGTCACTGTCCAACGATGA
TATTAACAAGATCTCAGGAGACATGAAAGACTCGCTTAAAGAGATGAGTCTGGAAG
AGATCTATTCTTATGAGAAGTATGGCGAGTTTATTACCCAAGAAGGAATCTCATTCT
ACAATGATATTTGTGGAAAGGTGAACAGCTTTATGAATCTTTACTGCCAAAAAAACA
AGGAGAATAAGAATCTTTACAAACTTCAGAAGTTACATAAACAGATTTTGTGTATTG
CGGATACGTCTTATGAAGTCCCCTACAAATTTGAATCGGATGAAGAGGTATACCAAA
GTGTGAACGGATTCTTGGACAATATTTCTTCTAAACATATTGTTGAACGCTTACGTA
AGATCGGGGATAACTACAATGGCTACAATCTTGACAAAATCTACATTGTTAGCAAAT
TCTACGAGAGTGTCAGCCAAAAGACGTACCGCGATTGGGAAACAATTAATACTGCG
CTTGAGATTCACTATAATAACATTTTACCAGGCAACGGCAAGTCCAAGGCGGATAA
AGTTAAAAAAGCTGTTAAAAACGATTTGCAAAAATCTATCACAGAAATTAACGAGT
TAGTTAGTAACTACAAACTGTGCTCCGATGACAACATTAAGGCTGAGACGTATATCC
ATGAGATCTCTCACATCTTAAACAATTTTGAAGCTCAAGAACTTAAGTACAATCCGG
AAATCCACCTGGTGGAATCCGAGCTGAAGGCTAGCGAACTGAAGAACGTATTGGAC
GTGATCATGAACGCGTTCCACTGGTGTTCTGTCTTTATGACGGAAGAGCTTGTCGAC
AAAGATAATAACTTTTACGCGGAACTTGAGGAAATTTACGATGAGATTTACCCAGTT
ATTTCATTGTATAACCTTGTCCGTAATTACGTGACCCAAAAGCCTTATAGTACGAAA
AAAATCAAATTAAATTTTGGAATCCCAACACTGGCTGACGGTTGGAGCAAATCTAA
GGAGTATTCTAATAACGCAATCATCTTAATGCGTGACAACCTGTATTATTTGGGTAT
CTTCAATGCCAAAAATAAGCCTGACAAAAAGATTATCGAAGGAAATACTTCGGAGA
ATAAGGGGGATTACAAAAAAATGATTTACAATTTGCTGCCCGGGCCGAACAAGATG
ATCCCCAAAGTGTTCTTATCCTCGAAGACTGGTGTAGAAACATACAAGCCAAGCGCA
TACATTCTGGAGGGTTACAAGCAAAACAAACACATCAAATCTTCAAAAGACTTTGA
CATTACATTTTGCCATGATCTTATTGACTACTTCAAAAACTGCATTGCTATTCACCCC
GAGTGGAAGAACTTTGGGTTTGACTTCAGCGACACGTCTACGTATGAGGACATCTCC
GGGTTCTACCGTGAAGTTGAGTTACAAGGGTATAAGATTGACTGGACGTATATTTCA
GAGAAAGATATCGATCTTTTGCAGGAAAAGGGCCAGTTATATTTATTCCAGATTTAC
AACAAGGACTTTAGTAAGAAGTCAACAGGAAATGACAACTTGCATACGATGTATTT
GAAAAATCTTTTTTCTGAGGAAAATCTTAAGGACATCGTACTGAAATTGAATGGCGA
GGCTGAAATCTTCTTCCGTAAATCCTCCATTAAGAATCCCATTATCCACAAAAAGGG
GTCTATCCTGGTGAATCGTACCTACGAGGCAGAGGAGAAGGATCAATTCGGAAATA
TTCAGATTGTTCGTAAGAACATCCCCGAGAACATTTATCAAGAATTGTATAAGTACT
TTAATGACAAATCTGACAAAGAGTTATCCGACGAAGCTGCGAAACTGAAAAACGTT
GTTGGTCACCACGAGGCCGCCACTAATATCGTAAAAGACTACCGTTATACCTATGAC
AAGTACTTTTTGCACATGCCGATCACTATCAACTTCAAGGCGAATAAGACGGGCTTC
ATTAACGATCGTATCCTGCAATACATCGCCAAGGAGAAGGACCTTCACGTCATTGGG
ATTGACCGTGGTGAGCGTAACCTGATTTATGTAAGCGTCATTGATACCTGCGGTAAT
ATCGTCGAACAGAAAAGTTTCAACATTGTAAATGGATATGACTATCAGATCAAACTT
AAGCAGCAGGAGGGTGCACGCCAGATTGCCCGCAAGGAATGGAAGGAGATTGGGA
AGATTAAGGAAATTAAAGAAGGTTACTTATCACTGGTTATTCACGAGATCAGTAAA
ATGGTAATCAAATATAACGCGATCATTGCCATGGAGGATCTGAGCTATGGCTTTAAA
AAGGGCCGTTTCAAAGTCGAGCGCCAGGTATATCAAAAGTTTGAAACAATGCTGAT
TAACAAATTAAACTATCTGGTTTTCAAAGATATTTCGATCACTGAAAATGGCGGGCT
GTTGAAGGGATACCAACTTACATACATCCCTGACAAACTGAAAAATGTCGGTCACC
AATGTGGATGTATCTTTTATGTACCAGCAGCGTATACGAGCAAAATCGATCCAACTA
CGGGTTTTGTGAACATCTTTAAGTTCAAGGATTTGACAGTAGATGCCAAACGCGAGT
TCATTAAAAAATTTGATTCAATTCGCTACGATTCAGAGAAAAATCTTTTTTGTTTCAC
GTTCGATTACAATAATTTCATTACGCAGAACACAGTAATGTCAAAGTCAAGCTGGTC
GGTCTACACGTATGGAGTCCGTATTAAACGTCGTTTTGTAAACGGCCGTTTCTCAAA
TGAATCAGATACAATTGATATTACGAAGGATATGGAGAAGACATTAGAGATGACTG
ACATTAACTGGCGCGACGGACATGATCTTCGTCAGGACATTATTGATTATGAGATTG
TACAGCATATCTTTGAGATCTTCCGCCTGACCGTTCAGATGCGCAATTCGTTGTCCGA
GTTAGAAGACCGCGATTACGACCGTTTAATCAGTCCCGTCTTAAACGAAAATAACAT
CTTCTACGATTCAGCCAAGGCAGGCGATGCCTTGCCAAAGGATGCTGACGCAAATG
GCGCATACTGTATTGCGTTGAAAGGCCTTTATGAAATCAAGCAAATTACCGAAAACT
GGAAAGAAGACGGAAAATTCTCCCGTGATAAGTTGAAAATCTCTAATAAGGATTGG
TTCGATTTCATCCAAAATAAACGCTATTTGAAACGTCCGGCAGCGACCAAAAAAGCC
GGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAAGA
AACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 96
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGAACTA
ATAATTTCCAAAATTTTATAGGCATCTCTTCTTTACAGAAGACTCTTCGTAACGCCCT
AATCCCGACTGAGACCACACAACAATTCATAGTGAAAAATGGGATCATTAAAGAAG
ACGAGCTGCGTGGGGAGAACAGGCAGATCCTAAAAGACATAATGGACGATTATTAT
AGAGGGTTCATCTCAGAGACATTATCTAGCATCGACGACATTGACTGGACCTCCCTG
TTTGAAAAAATGGAAATCCAGCTGAAGAATGGTGACAATAAAGACACATTAATAAA
AGAACAAACAGAGTACAGGAAAGCCATCCACAAGAAGTTCGCAAACGATGACAGA
TTCAAAAATATGTTCAGTGCGAAGCTAATATCCGACATCTTACCAGAGTTTGTAATA
CACAATAACAATTACAGCGCGAGCGAAAAGGAAGAGAAAACGCAAGTAATTAAGC
TTTTTAGTAGGTTCGCTACCTCTTTCAAAGATTACTTCAAAAATCGTGCTAACTGCTT
CTCAGCCGACGACATATCTTCAAGTTCCTGTCACCGTATCGTGAATGATAACGCTGA
GATATTCTTCTCAAACGCCCTTGTATACCGTAGGATCGTAAAGTCCTTATCTAACGAT
GATATAAACAAGATCAGTGGAGACATGAAAGACAGCCTTAAAGAGATGTCTCTAGA
AGAAATTTACTCCTATGAAAAGTATGGGGAGTTTATAACACAGGAGGGGATCAGCT
TCTACAACGACATCTGCGGAAAGGTGAACAGTTTCATGAATCTTTACTGCCAGAAGA
ATAAAGAGAACAAAAATCTTTATAAGCTTCAAAAGTTGCACAAACAAATACTGTGC
ATTGCCGATACATCATATGAGGTCCCCTATAAGTTCGAATCTGATGAGGAAGTTTAT
CAATCTGTTAACGGCTTTCTAGACAATATCAGCTCAAAACACATCGTAGAAAGACTG
AGGAAAATAGGTGATAATTATAATGGATACAACTTGGATAAAATATATATAGTCTCT
AAATTTTACGAGTCAGTATCCCAGAAAACGTATAGGGATTGGGAGACCATCAACAC
GGCGTTAGAGATTCATTACAATAACATCTTACCGGGAAACGGAAAAAGTAAGGCGG
ACAAAGTAAAGAAAGCCGTTAAAAATGACTTACAAAAGAGTATAACAGAAATAAA
CGAACTAGTAAGCAACTACAAGCTTTGTTCCGATGATAATATCAAGGCCGAGACAT
ATATCCATGAGATCTCCCACATTCTAAACAATTTCGAAGCGCAAGAACTTAAATATA
ATCCCGAAATCCACCTGGTGGAAAGTGAACTAAAGGCTAGTGAGTTAAAGAACGTT
CTTGATGTTATCATGAACGCCTTCCATTGGTGCTCTGTTTTTATGACCGAGGAGTTGG
TTGATAAAGATAATAATTTCTACGCTGAATTAGAGGAGATATACGACGAAATCTACC
CAGTGATTTCACTATACAACTTGGTCAGGAACTATGTTACACAAAAGCCGTACAGCA
CTAAGAAAATTAAGCTAAATTTCGGTATCCCCACGTTAGCCGACGGGTGGAGCAAG
TCCAAAGAATATTCCAACAATGCGATTATTTTAATGCGTGACAATCTTTATTACCTTG
GCATCTTCAATGCCAAAAACAAACCTGACAAAAAGATTATAGAAGGTAATACGTCC
GAGAACAAAGGCGATTACAAGAAGATGATTTATAACCTACTGCCCGGACCAAACAA
AATGATCCCCAAAGTTTTTCTTAGTTCTAAAACCGGCGTAGAGACGTATAAACCTTC
TGCCTATATCTTAGAGGGATATAAGCAGAACAAACATATCAAATCTTCCAAGGACTT
TGATATTACATTCTGCCACGATTTAATTGACTACTTCAAAAATTGCATAGCGATACA
TCCGGAGTGGAAGAACTTTGGCTTCGACTTCAGTGATACATCCACCTATGAGGATAT
ATCAGGCTTCTATCGTGAGGTCGAATTGCAAGGGTACAAAATCGATTGGACGTATAT
ATCCGAGAAAGACATAGACCTTCTTCAAGAAAAGGGGCAGTTATATTTATTCCAAAT
ATACAACAAGGACTTCAGTAAGAAGTCAACAGGTAATGACAACTTACACACCATGT
ACTTGAAAAATTTATTTTCTGAAGAAAACCTAAAGGACATTGTACTAAAACTGAACG
GGGAGGCAGAAATTTTTTTTAGAAAGAGCAGCATAAAAAACCCAATAATTCATAAG
AAAGGAAGCATTTTAGTTAATAGGACGTACGAGGCAGAGGAAAAGGACCAGTTTGG
CAATATCCAGATCGTAAGGAAAAATATTCCTGAAAACATATATCAGGAACTATATA
AATACTTTAACGACAAATCCGACAAAGAATTATCCGACGAGGCTGCAAAGCTGAAG
AACGTCGTAGGGCACCATGAGGCAGCGACTAATATTGTGAAAGACTATAGGTATAC
ATACGACAAATACTTTCTGCACATGCCCATCACGATTAACTTCAAGGCGAACAAGAC
GGGATTCATTAACGACCGTATATTACAATATATTGCTAAGGAGAAAGATCTGCATGT
AATAGGTATCGACAGAGGCGAACGTAATTTAATCTACGTGTCCGTCATCGACACGTG
CGGGAACATCGTAGAGCAAAAGAGTTTTAATATAGTAAATGGCTATGATTACCAAA
TTAAGCTAAAGCAGCAAGAAGGAGCAAGACAGATAGCTAGGAAAGAATGGAAGGA
GATAGGAAAAATAAAGGAGATCAAGGAGGGGTATCTTAGCCTAGTAATTCATGAAA
TATCTAAGATGGTTATCAAATACAACGCTATCATAGCGATGGAAGACTTATCTTATG
GTTTCAAGAAAGGAAGGTTCAAAGTAGAGCGTCAAGTTTATCAAAAGTTCGAAACG
ATGTTGATTAATAAACTAAACTATTTGGTATTTAAAGATATATCTATCACCGAGAAT
GGTGGTCTACTAAAGGGTTACCAGCTTACATACATACCGGACAAACTTAAAAACGTC
GGACATCAGTGTGGATGCATTTTCTACGTTCCAGCTGCATATACCAGCAAGATCGAC
CCAACGACTGGGTTCGTAAATATTTTTAAATTCAAGGATTTGACTGTCGACGCCAAA
AGAGAGTTCATAAAAAAGTTCGATTCAATTAGGTACGACAGCGAAAAGAATTTGTT
CTGCTTTACTTTTGACTATAACAATTTCATTACTCAGAACACTGTAATGTCTAAGTCC
TCTTGGTCAGTCTATACTTATGGCGTTCGTATCAAACGTAGATTTGTTAACGGTAGAT
TCTCAAATGAAAGTGATACAATAGATATCACGAAAGATATGGAGAAAACATTAGAA
ATGACAGACATAAACTGGAGAGACGGACATGACTTGAGACAGGACATTATTGACTA
CGAGATCGTGCAGCACATCTTTGAGATCTTTCGTTTGACCGTACAAATGCGTAACAG
TTTATCTGAGCTTGAGGACAGGGACTACGATAGATTGATATCACCTGTATTAAATGA
GAATAACATCTTCTATGATTCCGCAAAAGCAGGCGACGCTCTACCCAAAGACGCTG
ATGCGAACGGTGCTTATTGCATAGCTTTAAAGGGTTTGTATGAGATCAAACAGATAA
CAGAAAATTGGAAGGAAGATGGTAAGTTCTCCCGTGACAAGCTTAAAATATCAAAT
AAGGACTGGTTCGATTTTATACAGAATAAGCGTTATTAAAACGTCCGGCAGCGACCA
AAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCC
GAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCT
AA
SEQ ID NO: 97
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAATGGAACTA
ATAACTTCCAGAATTTCATTGGTATCTCCTCTTTACAAAAAACTCTAAGAAACGCCC
TAATTCCGACTGAAACTACACAGCAATTCATCGTCAAAAACGGGATCATTAAGGAG
GATGAGTTGAGGGGTGAAAATCGTCAAATTCTTAAAGACATCATGGACGACTACTA
CAGGGGGTTCATCAGCGAGACGTTATCTAGTATAGACGATATAGACTGGACTTCACT
GTTCGAGAAGATGGAAATCCAATTAAAAAATGGGGACAATAAAGATACACTTATAA
AGGAACAGACAGAGTATAGAAAGGCAATACACAAAAAGTTTGCCAACGACGATCGT
TTCAAGAACATGTTTAGTGCTAAATTGATTTCAGATATTCTGCCGGAATTTGTTATTC
ACAACAATAATTATAGCGCCAGTGAGAAAGAAGAAAAAACGCAGGTTATCAAACTG
TTCAGTCGTTTCGCTACATCTTTTAAGGATTACTTTAAAAACCGTGCAAATTGTTTTT
CAGCCGACGATATTAGTAGCAGCTCTTGTCACCGTATTGTTAATGATAATGCGGAGA
TTTTCTTTTCAAACGCATTGGTCTACAGGAGGATAGTCAAGTCCCTTTCAAATGACG
ACATTAATAAGATCTCAGGTGACATGAAAGATTCCTTAAAGGAAATGTCCCTGGAA
GAGATCTATTCCTATGAAAAGTACGGTGAGTTCATTACTCAAGAGGGTATAAGCTTT
TACAATGACATATGTGGTAAGGTTAATAGCTTTATGAACCTGTATTGCCAGAAGAAC
AAAGAAAATAAGAATCTGTATAAGTTGCAAAAGCTACACAAACAAATTTTGTGCAT
TGCCGATACATCATACGAGGTGCCATACAAATTCGAGAGCGATGAGGAGGTTTATC
AGAGCGTGAATGGATTCCTGGACAATATTAGTAGTAAGCATATCGTGGAAAGGCTT
AGAAAGATAGGTGACAATTACAATGGCTACAATCTGGATAAAATCTACATCGTCTC
AAAATTCTATGAAAGTGTATCCCAGAAGACGTACCGTGATTGGGAAACTATCAACA
CCGCTCTGGAGATACATTACAACAATATACTTCCCGGAAACGGCAAGTCAAAAGCC
GACAAAGTCAAAAAAGCGGTCAAGAACGATTTACAAAAGTCTATCACTGAAATTAA
TGAATTAGTTAGTAATTACAAACTGTGTAGTGATGATAATATTAAGGCAGAGACTTA
CATACACGAAATTTCACACATTTTAAACAACTTCGAGGCACAGGAACTTAAATATAA
TCCTGAAATTCACCTGGTTGAAAGTGAATTGAAAGCCAGCGAGCTAAAGAACGTTTT
GGACGTAATCATGAACGCATTCCACTGGTGCTCTGTCTTTATGACAGAGGAACTAGT
GGATAAGGACAATAATTTTTATGCGGAGCTGGAGGAAATATACGATGAGATATATC
CCGTAATATCATTATATAATCTGGTAAGAAACTATGTGACTCAAAAGCCGTATAGCA
CCAAGAAAATTAAACTTAATTTCGGCATACCCACTTTAGCGGACGGCTGGTCAAAAT
CCAAAGAGTATAGTAATAATGCCATCATCCTGATGCGTGACAACCTGTACTATTTAG
GTATATTTAACGCCAAAAATAAACCCGACAAAAAGATTATAGAGGGCAACACCTCA
GAGAACAAAGGTGATTATAAGAAGATGATTTACAACCTTTTACCCGGTCCTAATAAG
ATGATTCCCAAAGTCTTTCTATCTAGCAAAACTGGTGTTGAAACATACAAACCCTCA
GCTTATATTTTAGAAGGGTATAAGCAGAATAAGCATATTAAAAGCTCCAAAGATTTC
GATATTACCTTTTGCCATGACTTGATAGACTATTTCAAAAATTGTATTGCCATTCACC
CTGAATGGAAAAACTTCGGATTTGACTTCTCTGACACATCCACCTACGAAGACATTT
CAGGTTTTTACAGGGAAGTCGAGCTACAGGGTTATAAAATTGATTGGACATACATCA
GCGAGAAAGATATTGACCTACTTCAAGAAAAAGGGCAGCTATACCTGTTCCAGATA
TACAATAAAGACTTCAGTAAAAAAAGCACCGGGAACGATAATCTTCACACAATGTA
CTTAAAAAATTTATTTAGTGAAGAGAATCTGAAGGATATAGTGCTGAAGTTAAACG
GGGAGGCAGAGATATTTTTTAGAAAATCTAGTATTAAGAATCCGATCATCCACAAG
AAGGGTTCTATCCTTGTTAATAGGACTTATGAGGCAGAAGAAAAAGACCAATTCGG
CAACATACAAATTGTCCGTAAAAATATCCCTGAGAACATTTATCAGGAACTATACAA
GTACTTCAATGATAAAAGCGACAAGGAGCTGAGCGACGAGGCTGCTAAGTTAAAGA
ATGTGGTGGGCCACCATGAGGCAGCAACGAATATTGTGAAGGACTATCGTTATACCT
ACGATAAATACTTTCTTCATATGCCGATCACCATTAATTTCAAGGCAAACAAAACTG
GCTTCATTAACGATCGTATCTTACAATATATCGCAAAAGAGAAAGACCTTCACGTTA
TCGGGATCGATAGAGGCGAGCGTAACCTAATTTATGTTTCTGTGATAGACACCTGTG
GGAACATAGTCGAACAGAAATCATTTAATATTGTTAACGGCTACGATTATCAGATAA
AGTTGAAGCAACAAGAGGGTGCACGTCAAATAGCAAGGAAAGAATGGAAAGAAAT
AGGCAAGATTAAAGAAATAAAAGAAGGTTATTTATCCCTTGTAATACACGAAATTA
GCAAAATGGTGATTAAATATAATGCGATCATTGCCATGGAGGATCTTTCTTACGGCT
TCAAAAAGGGGAGATTCAAAGTCGAGAGGCAGGTGTATCAGAAGTTTGAGACCATG
CTAATCAATAAACTAAATTATCTAGTATTCAAAGACATAAGCATCACCGAAAATGGC
GGCTTGTTGAAGGGTTATCAATTGACCTACATCCCAGATAAACTAAAAAACGTAGG
GCATCAATGCGGATGTATATTTTACGTTCCAGCCGCATACACTTCCAAAATCGATCC
AACTACGGGTTTTGTGAACATCTTCAAATTCAAAGACTTGACTGTCGATGCTAAGAG
GGAGTTTATCAAGAAATTTGACTCCATTAGATACGACAGTGAGAAGAATCTGTTCTG
TTTTACCTTTGATTATAACAACTTTATAACTCAAAACACAGTCATGAGTAAGTCATCT
TGGTCAGTGTATACGTATGGTGTGAGGATTAAAAGGAGGTTTGTTAACGGGAGATTT
TCCAATGAAAGTGATACAATAGATATAACCAAGGACATGGAAAAGACTCTTGAAAT
GACCGACATTAACTGGAGAGATGGCCACGACTTACGTCAAGATATAATCGATTACG
AGATAGTGCAACATATCTTTGAGATATTTAGGCTTACTGTCCAAATGCGTAACTCAT
TAAGTGAGTTGGAGGACAGGGATTACGATAGGCTAATAAGTCCTGTTCTTAACGAA
AACAATATATTCTACGATTCAGCAAAGGCGGGAGACGCCCTGCCCAAGGACGCGGA
TGCTAACGGCGCATACTGTATTGCCCTGAAAGGCTTGTACGAGATAAAACAGATCAC
GGAGAACTGGAAAGAAGATGGAAAATTCAGTCGTGACAAGTTAAAAATTAGTAACA
AAGACTGGTTCGACTTTATTCAGAACAAGAGATATCTGAAACGTCCGGCAGCGACC
AAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCC
CGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGG
CTAA
SEQ ID NO: 98
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAACGGAACCA
ATAACTTTCAAAACTTTATAGGCATCTCCAGTCTACAGAAGACACTACGTAACGCTT
TGATACCAACTGAGACCACGCAGCAGTTTATCGTCAAGAACGGTATTATAAAGGAA
GACGAGCTAAGGGGGGAAAACCGTCAGATCTTAAAGGACATCATGGATGACTACTA
CAGAGGCTTCATAAGTGAGACTTTGTCTAGTATAGACGACATCGACTGGACCAGTTT
ATTTGAGAAGATGGAAATTCAGTTAAAGAACGGGGACAATAAAGACACACTAATTA
AAGAGCAGACCGAATACAGAAAAGCTATACACAAAAAGTTTGCCAACGATGATAGA
TTCAAAAATATGTTTTCAGCAAAATTGATTTCCGACATATTGCCAGAATTCGTAATC
CATAATAACAATTATTCTGCAAGTGAGAAGGAAGAGAAGACCCAAGTAATCAAGCT
GTTTTCCCGTTTTGCTACGAGTTTCAAAGATTATTTCAAGAATAGGGCTAATTGTTTC
TCCGCGGACGACATAAGTAGCAGTTCCTGTCACAGGATTGTGAACGATAATGCTGA
GATATTTTTTTCCAATGCCCTAGTGTATAGGAGAATAGTTAAAAGCTTAAGCAACGA
CGATATCAATAAAATTTCAGGGGACATGAAGGACAGCTTAAAGGAAATGAGTTTGG
AGGAGATTTACAGTTATGAAAAATACGGAGAGTTTATAACTCAGGAAGGCATCTCTT
TCTATAATGATATCTGTGGGAAGGTAAACTCCTTCATGAATTTATATTGCCAGAAGA
ATAAGGAAAACAAAAATCTTTACAAGCTTCAAAAGTTACATAAGCAGATCTTATGT
ATTGCCGACACGAGTTATGAAGTGCCTTATAAATTCGAGAGTGATGAGGAAGTGTAT
CAGTCTGTTAACGGATTCCTAGATAATATAAGTTCCAAACATATAGTCGAGAGGCTG
AGGAAGATTGGCGATAACTATAATGGATATAATCTTGACAAAATCTATATAGTCTCT
AAATTTTATGAAAGCGTCAGCCAGAAGACATATAGAGATTGGGAAACTATAAACAC
AGCCCTTGAAATACATTACAATAACATCCTACCCGGCAATGGTAAGTCTAAGGCAG
ACAAAGTTAAAAAAGCAGTAAAGAATGACTTACAGAAGTCAATCACGGAGATAAAT
GAGTTGGTCAGTAACTACAAATTATGCTCCGACGATAATATTAAGGCCGAAACATAT
ATACACGAGATAAGTCATATATTAAACAATTTCGAAGCCCAGGAGTTAAAATATAA
CCCTGAAATTCATCTGGTCGAAAGTGAGTTAAAGGCCAGTGAGTTAAAGAATGTACT
TGACGTAATTATGAATGCTTTTCATTGGTGCTCCGTGTTCATGACCGAGGAGTTAGT
AGATAAAGACAATAACTTTTACGCCGAACTTGAAGAGATATACGACGAGATTTATC
CGGTAATCAGCTTGTACAACTTAGTTAGAAATTATGTAACACAGAAGCCTTACTCTA
CTAAAAAAATAAAACTGAACTTTGGTATCCCAACTCTTGCAGATGGTTGGAGTAAAA
GCAAGGAATATAGCAACAATGCGATCATCTTGATGAGAGACAACTTGTACTATTTGG
GAATCTTCAACGCGAAAAATAAACCCGACAAAAAAATCATCGAAGGGAATACCTCT
GAGAATAAAGGTGACTATAAGAAAATGATTTACAATCTACTTCCTGGTCCTAATAAA
ATGATCCCGAAAGTGTTTCTTAGTTCTAAGACTGGTGTCGAGACGTACAAACCTAGC
GCGTACATCTTAGAAGGGTACAAGCAGAATAAACACATCAAATCAAGCAAAGACTT
CGATATTACTTTTTGCCATGACTTGATAGACTACTTTAAAAACTGCATAGCAATCCA
CCCGGAGTGGAAAAACTTTGGCTTTGATTTCTCTGACACCTCTACATATGAGGACAT
ATCTGGTTTTTACCGTGAGGTTGAATTGCAGGGATACAAAATTGACTGGACTTACAT
ATCTGAAAAAGATATCGATCTATTGCAGGAGAAAGGCCAGCTTTACCTTTTCCAGAT
CTATAATAAGGACTTCTCTAAGAAGTCTACAGGGAATGATAATTTGCACACTATGTA
CTTAAAAAATCTGTTTTCCGAGGAAAACTTGAAAGACATTGTTTTAAAGTTGAACGG
AGAAGCTGAAATATTTTTCAGAAAGAGCTCCATAAAAAACCCGATCATTCATAAGA
AGGGATCTATCCTGGTTAACAGAACGTACGAAGCGGAAGAAAAAGACCAATTCGGA
AACATTCAAATTGTTAGAAAGAATATCCCTGAGAACATCTACCAGGAGTTATATAAG
TATTTTAATGATAAGTCAGATAAGGAACTATCTGACGAAGCGGCGAAGCTTAAAAA
TGTTGTAGGACACCATGAGGCTGCTACAAATATAGTCAAGGACTACCGTTATACCTA
CGATAAGTACTTTCTACACATGCCCATTACCATCAATTTTAAAGCTAATAAAACGGG
TTTTATCAACGATCGTATCCTACAATATATTGCGAAAGAGAAGGATTTGCATGTCAT
TGGCATTGATAGAGGTGAGAGGAACCTAATATACGTATCCGTGATTGATACGTGCG
GGAACATAGTTGAACAGAAATCATTTAATATAGTTAATGGGTACGACTATCAGATTA
AGCTAAAGCAACAAGAAGGCGCCAGGCAAATTGCCCGTAAAGAATGGAAAGAGAT
CGGGAAGATCAAGGAAATAAAAGAAGGATACCTTTCCCTGGTCATCCATGAAATTA
GCAAAATGGTGATTAAGTACAATGCCATAATCGCGATGGAGGACTTAAGCTACGGG
TTCAAAAAGGGGAGGTTTAAGGTGGAGAGGCAAGTGTACCAGAAATTTGAGACCAT
GCTAATCAACAAACTGAACTACCTAGTTTTTAAGGACATTTCAATTACAGAGAATGG
AGGACTTTTAAAGGGTTACCAACTAACGTATATACCAGATAAGTTGAAAAATGTCG
GTCACCAGTGTGGCTGCATCTTTTACGTTCCCGCCGCTTATACATCTAAAATTGATCC
AACCACAGGCTTTGTAAATATCTTTAAATTCAAAGATTTAACTGTGGATGCAAAAAG
AGAGTTTATCAAGAAATTCGATAGCATTCGTTATGATAGCGAGAAGAACCTGTTCTG
CTTTACTTTCGACTATAACAACTTTATAACTCAAAACACCGTGATGTCAAAAAGCTC
ATGGTCAGTCTACACCTATGGTGTAAGGATTAAAAGGCGTTTCGTGAATGGGAGATT
CTCCAATGAAAGTGACACGATCGACATAACAAAGGACATGGAGAAGACACTAGAG
ATGACTGATATTAATTGGAGAGACGGACACGATCTGCGTCAAGATATAATTGATTAT
GAGATAGTACAGCACATATTTGAGATCTTCCGTTTGACTGTCCAAATGCGTAATTCC
CTTTCTGAGCTGGAAGATAGGGACTATGATAGATTAATATCCCCTGTACTAAATGAG
AACAACATTTTCTATGATAGTGCAAAAGCCGGGGATGCATTGCCGAAAGACGCTGA
CGCTAATGGGGCGTACTGTATAGCTTTAAAGGGGCTTTACGAAATAAAGCAGATAA
CCGAAAACTGGAAGGAAGATGGCAAATTCTCAAGGGACAAACTTAAGATCTCTAAC
AAGGATTGGTTCGATTTTATACAAAACAAACGTTATTTGAAACGTCCGGCAGCGACC
AAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCC
CGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGG
CTAA
SEQ ID NO: 99
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAATGGTACAAA
CAACTTTCAGAATTTCATTGGGATCTCTAGCTTACAGAAGACCCTGAGGAATGCGTT
GATTCCAACTGAAACAACCCAGCAATTCATCGTGAAAAATGGGATAATCAAAGAGG
ATGAGTTAAGGGGTGAAAACCGTCAAATATTGAAGGATATTATGGACGACTACTAC
CGTGGATTCATCTCAGAGACGTTGAGCAGCATTGACGACATAGACTGGACTAGCCTT
TTCGAGAAGATGGAAATTCAGTTAAAGAACGGAGATAACAAAGATACACTAATCAA
GGAACAGACAGAATACAGAAAAGCAATTCATAAGAAATTCGCTAATGACGATCGTT
TTAAAAACATGTTCTCTGCAAAATTAATTAGCGACATTCTGCCGGAATTCGTTATAC
ATAATAATAACTACAGTGCTTCTGAAAAGGAAGAGAAAACTCAGGTAATAAAACTG
TTCTCTCGTTTTGCCACATCCTTCAAAGACTACTTTAAAAATAGAGCGAACTGCTTTA
GCGCCGACGATATTAGTTCTTCCTCATGCCACAGGATTGTCAACGATAATGCAGAGA
TATTCTTTTCTAACGCACTAGTCTACAGAAGGATTGTAAAGTCTTTGTCAAATGATG
ACATAAACAAGATTAGTGGAGATATGAAAGACTCTCTAAAGGAAATGAGCCTTGAG
GAGATATACTCTTATGAAAAGTACGGTGAGTTTATTACCCAAGAAGGCATTAGTTTC
TATAATGACATTTGTGGAAAAGTTAACAGTTTTATGAATCTATACTGTCAAAAAAAT
AAGGAGAATAAAAATCTTTATAAGTTGCAAAAACTGCATAAGCAGATATTATGTAT
AGCAGACACGAGCTATGAGGTACCGTACAAGTTCGAGAGCGATGAGGAAGTCTACC
AATCTGTCAACGGATTTTTGGACAACATTTCTTCAAAACATATTGTGGAGAGGCTTA
GGAAAATAGGCGACAATTATAATGGATATAACTTAGATAAGATATATATTGTTTCCA
AATTCTACGAATCTGTAAGCCAGAAGACATACAGAGATTGGGAAACGATAAACACA
GCCCTTGAAATTCACTATAACAACATACTACCTGGAAACGGCAAATCAAAGGCCGA
CAAAGTTAAGAAGGCCGTAAAGAATGATTTACAGAAGAGCATAACGGAGATCAATG
AGCTGGTGTCTAACTATAAATTGTGTAGCGATGACAACATAAAAGCCGAGACTTAC
ATTCACGAAATTTCACACATACTTAACAACTTTGAAGCTCAGGAATTAAAGTATAAT
CCCGAAATACACCTTGTGGAGTCCGAACTAAAGGCTAGTGAGCTTAAGAACGTCCT
AGACGTAATTATGAATGCCTTCCACTGGTGTAGTGTTTTTATGACCGAGGAACTTGT
TGACAAAGATAATAATTTTTATGCAGAACTAGAAGAGATATACGATGAAATATACC
CGGTGATCAGTTTGTACAATCTTGTCAGGAACTATGTGACACAAAAGCCCTATTCAA
CAAAGAAAATAAAACTTAATTTCGGAATTCCTACGTTAGCTGATGGCTGGTCTAAAT
CCAAGGAATACAGCAACAACGCTATAATTCTGATGAGAGATAACTTGTACTATCTAG
GCATCTTCAATGCCAAAAATAAGCCTGATAAGAAGATTATAGAGGGCAACACTTCA
GAGAACAAGGGCGACTACAAGAAAATGATCTATAACCTATTGCCTGGCCCAAACAA
GATGATTCCGAAGGTCTTCCTATCATCCAAGACCGGCGTTGAGACATACAAGCCATC
AGCGTATATTTTAGAGGGGTACAAACAAAACAAGCACATAAAGTCTAGTAAAGACT
TCGATATAACATTTTGTCATGACTTAATTGACTACTTTAAGAATTGCATCGCTATACA
CCCGGAATGGAAGAATTTCGGCTTCGACTTCTCTGATACATCTACCTACGAGGACAT
TAGCGGGTTTTACCGTGAAGTCGAATTACAAGGGTATAAGATAGATTGGACGTACAT
CTCTGAGAAAGACATAGACTTGCTTCAGGAAAAGGGCCAGTTGTATCTATTCCAAAT
ATACAATAAGGATTTTTCCAAGAAATCTACGGGTAATGACAATCTTCACACAATGTA
TCTTAAGAACCTTTTCTCAGAAGAGAACCTGAAGGACATTGTCTTAAAACTAAATGG
CGAAGCTGAGATTTTTTTCAGGAAGTCTTCAATTAAGAACCCGATAATCCACAAGAA
GGGGAGTATTCTTGTGAATAGAACTTACGAGGCCGAAGAAAAAGACCAATTTGGTA
ACATCCAGATAGTCAGAAAGAACATTCCAGAGAACATCTACCAAGAGCTATACAAA
TATTTCAACGACAAGTCCGATAAGGAACTGTCCGATGAGGCAGCCAAGTTGAAGAA
TGTCGTGGGTCATCATGAAGCTGCTACTAACATTGTCAAGGACTATCGTTATACTTA
CGACAAGTATTTCCTACACATGCCGATAACAATTAATTTCAAGGCTAACAAAACAGG
CTTTATCAACGATCGTATCTTGCAGTACATAGCTAAGGAAAAGGATTTGCATGTGAT
TGGCATTGATAGAGGGGAGCGTAACTTGATATATGTGTCTGTCATAGACACGTGTGG
CAACATCGTCGAACAGAAATCATTCAACATAGTAAACGGCTACGATTACCAAATTA
AGCTGAAACAGCAAGAGGGTGCACGTCAAATTGCGCGTAAAGAGTGGAAAGAAATT
GGTAAAATCAAGGAAATTAAAGAAGGCTACTTGTCTCTTGTTATACATGAAATTTCC
AAGATGGTTATAAAGTATAACGCGATAATTGCTATGGAAGACTTATCATACGGGTTT
AAAAAGGGGAGGTTCAAGGTAGAGAGGCAGGTCTATCAAAAGTTCGAGACGATGTT
GATTAATAAACTAAACTATCTAGTGTTCAAAGATATCAGCATTACGGAGAACGGGG
GGCTACTGAAAGGATATCAACTAACGTACATTCCCGATAAGTTAAAGAACGTTGGTC
ATCAATGTGGTTGCATCTTCTACGTGCCTGCTGCCTATACGTCCAAAATAGATCCAA
CTACTGGATTTGTTAACATCTTTAAATTCAAAGATTTAACCGTAGACGCCAAAAGGG
AATTTATAAAAAAATTTGACAGCATCCGTTACGATAGCGAAAAGAATCTGTTCTGTT
TTACTTTCGACTACAATAATTTCATCACGCAAAATACGGTAATGTCTAAGTCAAGTT
GGAGCGTCTACACGTATGGAGTCAGGATCAAGAGGCGTTTCGTAAATGGAAGATTC
TCTAATGAGTCAGATACTATAGACATCACGAAAGATATGGAGAAAACCTTGGAGAT
GACGGATATTAACTGGCGTGATGGACACGATTTAAGACAGGACATTATTGACTATG
AGATTGTGCAACACATCTTCGAAATATTCCGTCTAACAGTCCAAATGAGGAATAGCC
TAAGTGAATTGGAGGACCGTGATTACGATAGGCTTATAAGTCCTGTCCTTAACGAAA
ACAATATTTTCTATGATAGTGCTAAGGCGGGGGACGCACTGCCTAAAGACGCAGAT
GCTAACGGGGCATACTGCATTGCGTTAAAGGGTCTGTACGAAATCAAGCAGATTAC
GGAAAACTGGAAAGAGGATGGCAAGTTTAGCAGAGATAAGTTGAAGATAAGTAAC
AAAGATTGGTTTGACTTTATTCAGAATAAAAGGTATTTAAAACGTCCGGCAGCGACC
AAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCC
CGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGG
CTAA
SEQ ID NO: 100
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGCACTAA
TAATTTCCAGAATTTCATCGGCATTAGCAGCTTACAAAAGACGTTGAGGAATGCCTT
AATACCCACAGAAACTACTCAACAATTTATAGTGAAGAATGGGATAATTAAGGAAG
ACGAGTTGAGAGGTGAAAATAGGCAAATCTTGAAAGACATTATGGATGACTACTAC
AGGGGCTTCATTAGTGAAACGTTGTCTTCAATAGATGACATTGATTGGACTTCTTTGT
TTGAGAAGATGGAAATACAGTTAAAGAACGGCGACAATAAGGATACACTTATCAAA
GAGCAAACAGAATATAGAAAAGCAATTCACAAAAAGTTTGCTAACGATGATAGGTT
CAAGAACATGTTTAGCGCTAAACTAATATCAGACATCCTTCCCGAGTTCGTTATTCA
TAACAATAACTATAGTGCAAGTGAAAAAGAGGAGAAGACACAGGTGATTAAGCTGT
TCTCCAGATTCGCGACTTCTTTCAAAGATTACTTCAAAAACAGAGCCAACTGTTTTTC
AGCTGACGATATCTCTAGTAGTAGTTGTCACCGTATAGTGAACGATAACGCTGAGAT
CTTCTTTAGCAATGCATTAGTGTATAGAAGGATAGTTAAGTCTCTAAGCAATGATGA
TATCAATAAAATTTCCGGAGACATGAAGGACTCCCTAAAGGAAATGTCCTTAGAAG
AGATCTACTCATATGAGAAATACGGGGAATTTATTACGCAGGAAGGGATCTCCTTTT
ACAATGACATATGCGGGAAGGTCAACTCTTTCATGAACTTATACTGCCAAAAGAAC
AAGGAGAACAAGAATTTATATAAACTTCAGAAACTTCACAAACAAATACTGTGCAT
AGCCGATACCTCATATGAGGTTCCTTACAAATTTGAATCAGATGAAGAGGTATACCA
ATCCGTTAACGGCTTTCTTGACAATATTAGCTCAAAGCACATCGTGGAGAGGTTGAG
AAAGATTGGTGATAATTATAATGGCTACAATCTAGATAAGATATATATTGTTAGCAA
GTTCTACGAGTCTGTGTCCCAAAAAACATATAGGGATTGGGAGACAATTAATACTGC
TCTAGAAATCCATTACAACAACATCCTTCCTGGAAATGGCAAGAGTAAGGCCGACA
AAGTCAAGAAAGCAGTGAAAAATGATCTGCAAAAATCAATTACTGAGATAAACGAG
CTAGTATCTAATTACAAGCTTTGTAGCGACGATAACATTAAGGCAGAAACGTACATA
CACGAGATTAGTCACATCTTAAATAATTTTGAAGCCCAAGAACTGAAATATAACCCT
GAGATACACCTTGTTGAATCCGAGTTAAAGGCGTCTGAACTAAAAAACGTGTTAGA
CGTTATTATGAATGCCTTCCACTGGTGTAGCGTCTTTATGACTGAGGAGTTGGTTGAT
AAGGATAATAACTTTTACGCTGAATTGGAAGAAATTTATGACGAAATCTATCCTGTT
ATTTCTCTATATAATTTGGTGAGAAATTACGTAACGCAAAAGCCCTATAGTACGAAA
AAAATAAAACTAAATTTCGGGATCCCTACCCTAGCCGACGGTTGGTCTAAATCCAAG
GAGTACTCAAACAATGCAATAATATTGATGAGGGACAACCTGTACTACCTAGGCAT
ATTTAATGCCAAAAATAAGCCCGATAAAAAGATTATAGAAGGGAACACGTCAGAAA
ATAAAGGAGACTATAAGAAAATGATCTACAACCTTTTGCCCGGCCCCAATAAAATG
ATCCCGAAGGTCTTCCTAAGTAGCAAGACTGGCGTAGAGACCTACAAACCATCTGC
ATACATTTTGGAGGGGTACAAGCAAAACAAGCACATAAAGAGTAGTAAGGATTTTG
ACATTACATTCTGCCATGACTTAATTGACTACTTTAAAAATTGCATCGCAATTCACCC
TGAATGGAAAAATTTTGGATTTGATTTCTCTGATACTTCAACATATGAGGATATTTCA
GGGTTCTACAGGGAGGTCGAACTACAGGGTTACAAAATAGACTGGACGTATATTTCT
GAGAAAGATATAGATTTGCTTCAGGAAAAGGGTCAGCTATATCTGTTCCAGATATAT
AATAAGGACTTCTCCAAAAAGAGTACCGGAAATGATAATCTGCACACAATGTACTT
AAAAAACTTGTTCTCTGAGGAGAATCTAAAAGACATCGTACTAAAACTTAACGGGG
AGGCCGAAATTTTTTTTAGGAAGTCCAGCATCAAGAACCCGATTATTCATAAAAAAG
GTAGCATTTTGGTGAACCGTACTTATGAGGCGGAAGAAAAAGACCAATTCGGTAAT
ATTCAAATCGTTAGAAAGAACATCCCTGAGAACATTTATCAGGAACTATACAAATAC
TTTAACGACAAATCAGATAAGGAGCTTTCTGATGAGGCAGCTAAATTGAAAAATGT
AGTGGGACATCACGAAGCAGCCACTAACATAGTGAAGGACTACAGATACACATACG
ATAAGTACTTCCTGCACATGCCTATTACAATTAACTTTAAAGCAAATAAAACAGGGT
TTATTAACGACAGAATCTTACAGTATATTGCCAAAGAAAAGGATCTGCATGTGATAG
GAATAGACAGAGGAGAAAGAAACCTGATATACGTCTCCGTGATTGATACATGTGGG
AACATAGTAGAACAGAAGTCCTTTAACATTGTTAATGGGTACGATTATCAAATTAAA
TTAAAACAACAAGAAGGAGCACGTCAAATAGCTAGGAAAGAATGGAAAGAGATAG
GAAAAATTAAGGAAATTAAGGAGGGTTACCTGTCCCTTGTAATTCATGAAATATCCA
AAATGGTAATTAAATATAACGCGATCATCGCGATGGAAGATCTAAGCTACGGGTTC
AAAAAAGGCAGGTTTAAGGTGGAGAGGCAAGTTTACCAAAAGTTCGAGACAATGTT
GATTAATAAGTTAAACTACTTAGTTTTCAAAGATATCTCCATAACCGAGAATGGCGG
GCTTTTAAAAGGGTACCAACTAACATATATCCCGGATAAATTGAAGAACGTTGGAC
ACCAGTGTGGCTGCATATTTTATGTACCCGCTGCGTATACTTCTAAAATTGACCCGA
CCACCGGGTTTGTAAACATATTCAAGTTTAAGGACCTAACAGTTGACGCCAAACGTG
AGTTCATCAAGAAGTTCGATAGTATAAGGTATGACTCTGAGAAGAACCTTTTCTGCT
TCACGTTTGACTATAATAATTTCATCACCCAAAATACAGTTATGTCAAAAAGCTCTT
GGTCAGTATATACGTATGGCGTAAGGATTAAGCGTAGGTTCGTGAACGGTAGATTTT
CCAACGAGTCAGATACTATTGATATTACCAAGGATATGGAGAAGACATTAGAAATG
ACAGATATAAATTGGAGGGATGGGCACGATCTAAGGCAAGATATCATTGATTACGA
AATTGTTCAGCACATATTCGAGATATTCCGTCTTACAGTACAAATGCGTAACAGCTT
GTCTGAGTTGGAAGATCGTGACTATGACAGGTTGATATCACCGGTCTTGAACGAGAA
CAATATATTCTACGACAGCGCTAAGGCGGGAGACGCTCTGCCTAAAGACGCAGATG
CCAATGGGGCGTACTGCATTGCCTTAAAAGGCTTATACGAGATTAAACAGATCACA
GAGAACTGGAAAGAGGACGGCAAGTTTTCTAGAGATAAATTGAAAATCTCAAACAA
AGACTGGTTCGATTTCATCCAAAACAAAAGATACCTTAAACGTCCGGCAGCGACCA
AAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCC
GAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCT
AA
SEQ ID NO: 101
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAATGGAACTA
ACAACTTCCAGAACTTTATCGGCATCTCTTCCCTCCAAAAGACACTGAGAAATGCAC
TGATCCCAACCGAAACGACTCAACAATTTATTGTTAAGAACGGCATCATAAAAGAA
GACGAGCTTCGCGGCGAGAACCGCCAGATACTTAAGGATATTATGGACGATTATTA
CCGAGGCTTTATCAGCGAAACTCTTAGCTCTATTGATGATATCGACTGGACCTCCCT
CTTCGAAAAAATGGAGATACAGCTCAAGAACGGCGATAATAAAGACACCTTGATAA
AGGAACAGACTGAGTACAGGAAAGCGATCCACAAGAAATTCGCGAACGACGACAG
GTTTAAAAACATGTTCTCTGCAAAATTGATATCCGACATCTTGCCGGAATTTGTGAT
ACACAACAATAACTATAGCGCTTCAGAGAAAGAAGAGAAGACCCAAGTAATCAAGT
TGTTCAGCCGCTTCGCAACGTCTTTTAAAGATTACTTTAAGAACCGGGCCAATTGTTT
CTCCGCGGATGATATTAGCTCATCAAGTTGCCATCGAATTGTCAATGATAATGCGGA
GATCTTCTTCAGCAATGCGCTGGTCTACAGACGAATCGTAAAAAGTCTTTCAAATGA
CGACATCAATAAGATTAGTGGAGATATGAAGGATTCCCTTAAGGAAATGAGTCTTG
AAGAAATATACTCATACGAAAAGTACGGGGAATTTATTACCCAGGAGGGGATCTCC
TTCTATAACGACATCTGTGGAAAAGTAAACTCATTCATGAACCTGTACTGTCAGAAA
AACAAAGAAAACAAAAATCTGTATAAACTCCAAAAATTGCACAAGCAAATATTGTG
TATAGCGGACACATCATACGAGGTTCCATATAAGTTCGAAAGTGATGAAGAAGTCT
ACCAATCAGTGAATGGGTTTCTGGACAACATTAGTTCCAAGCACATAGTTGAACGAC
TGCGAAAGATTGGTGACAATTACAACGGCTATAATTTGGACAAGATTTATATAGTTA
GCAAATTTTATGAATCCGTATCACAAAAGACTTATAGAGACTGGGAAACAATCAAC
ACGGCACTTGAGATCCATTATAACAATATTCTTCCAGGGAACGGCAAAAGCAAGGC
TGATAAGGTAAAAAAGGCCGTTAAGAATGATCTTCAAAAATCCATAACGGAGATCA
ACGAACTTGTAAGTAACTACAAATTGTGCTCTGACGACAATATAAAGGCTGAAACG
TATATTCACGAGATTAGCCATATCCTGAATAACTTTGAGGCCCAAGAACTCAAGTAT
AACCCGGAAATACATTTGGTAGAAAGCGAGCTTAAAGCGAGTGAGCTGAAAAACGT
CCTCGATGTGATCATGAATGCTTTCCACTGGTGTAGTGTCTTTATGACTGAGGAGTTG
GTTGATAAAGACAATAATTTCTACGCTGAACTGGAAGAAATTTACGACGAAATCTAT
CCAGTGATCTCCCTCTATAACCTCGTTCGAAACTACGTGACGCAGAAACCTTATTCT
ACAAAGAAAATTAAGTTGAACTTCGGCATTCCTACACTTGCTGACGGATGGTCCAAA
TCCAAAGAGTACTCAAACAACGCAATCATCCTCATGCGGGATAACCTTTATTATTTG
GGCATTTTCAACGCCAAAAACAAACCTGATAAAAAGATAATTGAAGGCAATACGAG
TGAGAACAAGGGCGACTACAAAAAAATGATATATAACTTGTTGCCAGGCCCCAACA
AGATGATTCCTAAAGTTTTTCTGTCTTCTAAGACTGGAGTTGAAACTTACAAACCCTC
CGCCTACATTCTTGAAGGGTATAAACAGAATAAGCACATAAAGTCCTCAAAGGATTT
CGACATTACGTTTTGCCATGACCTCATCGACTATTTCAAGAACTGTATCGCCATACAT
CCGGAGTGGAAGAATTTTGGATTTGATTTCTCCGACACATCTACCTATGAAGACATA
AGCGGTTTCTACCGGGAGGTCGAGCTTCAGGGCTATAAGATAGATTGGACATACATT
AGTGAAAAAGATATCGATCTTCTGCAAGAAAAGGGACAACTTTACCTTTTTCAGATT
TATAATAAAGACTTTTCAAAAAAGTCCACAGGGAACGATAATCTGCACACCATGTAT
CTCAAGAATCTGTTTAGTGAAGAAAACCTTAAAGACATAGTTTTGAAGCTTAACGGA
GAGGCTGAGATTTTTTTTAGAAAGTCCTCAATTAAAAACCCTATAATACACAAGAAA
GGCTCTATTCTTGTTAACAGGACATATGAAGCCGAGGAGAAAGATCAGTTTGGCAAT
ATCCAGATTGTTCGCAAGAATATCCCGGAAAATATATATCAGGAGCTGTATAAATAC
TTTAACGACAAGAGCGACAAGGAGCTGAGTGACGAGGCCGCGAAGCTTAAGAATGT
AGTAGGTCACCACGAAGCAGCCACCAATATCGTCAAAGACTATAGGTACACGTACG
ACAAGTACTTTTTGCACATGCCTATAACTATAAACTTCAAAGCTAATAAAACTGGGT
TTATTAATGACAGGATTCTCCAATACATCGCTAAAGAGAAGGATCTGCATGTAATTG
GCATAGACAGAGGTGAGAGAAACTTGATATATGTCAGCGTAATAGACACATGTGGC
AATATCGTGGAACAGAAGTCTTTTAACATCGTCAATGGTTACGACTACCAAATTAAG
TTGAAACAGCAGGAAGGCGCACGACAGATCGCACGAAAGGAATGGAAAGAGATAG
GCAAAATAAAAGAAATAAAGGAGGGCTATCTCAGTCTCGTTATACACGAAATTTCA
AAAATGGTTATTAAGTACAATGCAATCATAGCGATGGAGGATCTCAGTTATGGGTTC
AAAAAGGGTCGGTTTAAAGTTGAGCGCCAAGTGTACCAAAAGTTCGAGACAATGCT
GATTAACAAGCTGAACTACCTCGTCTTCAAAGATATAAGTATTACGGAGAACGGTG
GCCTTCTTAAAGGCTATCAACTTACTTACATCCCGGACAAGCTCAAAAACGTAGGGC
ACCAATGCGGGTGTATTTTCTATGTGCCTGCGGCATATACGTCAAAGATTGACCCAA
CCACAGGATTCGTAAACATATTCAAGTTTAAGGACCTCACCGTTGATGCGAAAAGG
GAGTTCATTAAAAAATTTGATTCTATTCGATATGATAGTGAGAAAAATCTCTTTTGTT
TCACATTTGACTATAATAATTTTATTACTCAGAATACTGTCATGAGCAAGTCATCTTG
GTCAGTGTACACATACGGGGTGCGGATCAAACGCAGGTTCGTCAATGGTCGCTTCTC
AAACGAATCAGACACCATTGACATCACAAAGGACATGGAAAAAACCCTTGAGATGA
CCGACATTAATTGGCGCGATGGTCATGATCTGCGGCAAGACATCATAGACTACGAA
ATCGTCCAACACATCTTTGAGATCTTTCGCTTGACGGTCCAAATGCGGAACTCCCTG
TCCGAGCTCGAGGATAGAGATTATGATCGGCTGATATCTCCCGTGCTTAATGAAAAT
AACATCTTCTACGACTCCGCCAAGGCGGGTGATGCCCTGCCGAAGGATGCGGATGCT
AATGGCGCTTATTGCATTGCTCTTAAGGGGCTCTATGAGATAAAGCAGATCACGGAA
AACTGGAAAGAAGACGGTAAGTTTAGTAGAGACAAGCTGAAGATCTCAAATAAAGA
CTGGTTTGATTTCATACAGAACAAGCGGTACCTGAAACGTCCGGCAGCGACCAAAA
AAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAA
AAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 102
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAACAATGGCACTAA
CAATTTTCAGAATTTCATCGGCATTTCAAGTCTGCAAAAAACTCTGAGGAATGCTTT
GATCCCTACTGAAACCACTCAGCAATTTATAGTCAAGAACGGTATAATTAAAGAAG
ATGAACTCAGGGGTGAAAATAGACAAATACTCAAGGACATTATGGATGACTATTAT
AGAGGCTTCATCTCAGAGACTCTCTCATCAATAGATGATATCGATTGGACTAGCCTT
TTCGAGAAAATGGAGATTCAGTTGAAAAATGGTGATAACAAAGATACGTTGATAAA
GGAACAGACCGAGTACAGGAAAGCCATTCATAAGAAATTTGCTAATGACGATAGAT
TTAAGAATATGTTTAGTGCAAAACTGATTAGTGACATTCTGCCGGAGTTCGTTATCC
ATAATAATAACTACTCTGCATCCGAAAAGGAGGAAAAGACGCAAGTTATTAAACTG
TTCAGCCGCTTCGCCACAAGCTTCAAGGACTACTTCAAAAATAGAGCCAACTGCTTT
TCTGCCGACGATATATCATCATCTTCATGCCATCGGATCGTTAACGATAACGCCGAG
ATATTCTTCAGCAACGCCCTTGTATATCGAAGAATAGTCAAAAGTCTGAGTAATGAT
GATATTAATAAAATTAGCGGTGATATGAAAGACTCCCTGAAGGAAATGTCACTGGA
GGAAATTTATAGTTACGAAAAGTACGGCGAATTCATTACTCAAGAAGGCATATCCTT
CTATAACGACATTTGCGGAAAGGTCAACTCATTCATGAACCTTTATTGCCAGAAGAA
TAAGGAGAATAAAAATCTTTACAAATTGCAAAAACTTCACAAACAAATTCTTTGCAT
CGCGGATACGTCCTACGAAGTTCCTTACAAATTTGAATCCGATGAGGAAGTGTATCA
GAGTGTCAATGGATTTTTGGATAATATCTCTTCAAAACATATTGTGGAGAGATTGCG
CAAAATAGGTGATAACTACAATGGCTACAACCTGGACAAGATTTATATTGTTAGCAA
GTTCTATGAAAGTGTCAGTCAAAAGACCTACAGAGATTGGGAGACAATCAACACGG
CGCTCGAAATACACTACAATAACATCCTCCCCGGCAATGGGAAGAGTAAAGCCGAT
AAGGTTAAAAAAGCTGTTAAGAACGACCTCCAGAAATCCATCACGGAAATAAACGA
GCTGGTTTCCAACTATAAGCTGTGTAGCGATGATAATATTAAGGCTGAGACATATAT
ACATGAGATCAGCCACATTCTCAACAATTTCGAGGCACAGGAACTCAAATACAATC
CCGAGATTCACTTGGTGGAAAGTGAGTTGAAGGCGTCAGAGCTTAAGAATGTACTT
GACGTAATAATGAATGCTTTTCATTGGTGCTCCGTGTTCATGACTGAGGAACTCGTG
GATAAGGATAATAACTTTTATGCGGAGTTGGAAGAGATATACGATGAAATATACCC
GGTTATCTCACTGTATAATCTGGTCAGAAATTACGTGACCCAAAAGCCTTATAGTAC
AAAAAAAATAAAGTTGAACTTCGGTATTCCGACATTGGCAGATGGTTGGTCCAAAA
GCAAAGAATACTCTAATAACGCCATTATATTGATGCGAGACAATTTGTATTACCTTG
GGATCTTTAACGCGAAAAACAAACCGGATAAGAAGATCATCGAAGGTAATACATCT
GAGAATAAGGGGGATTACAAGAAGATGATTTATAATCTGTTGCCGGGGCCAAACAA
GATGATTCCGAAGGTCTTTCTGTCATCTAAGACAGGAGTAGAGACCTACAAACCTTC
TGCGTACATTTTGGAAGGCTACAAACAGAACAAGCATATAAAATCTAGCAAGGACT
TTGATATCACGTTTTGTCATGATCTGATAGATTATTTCAAAAACTGCATCGCTATACA
TCCTGAGTGGAAGAATTTCGGCTTTGACTTTTCTGACACCAGCACATACGAAGACAT
CTCAGGTTTCTACCGGGAAGTCGAGCTCCAGGGGTACAAGATTGACTGGACATATAT
AAGTGAAAAAGACATCGACCTCCTCCAAGAGAAGGGCCAACTTTACCTGTTCCAGA
TCTATAACAAAGACTTTTCTAAAAAGTCCACGGGTAACGACAACTTGCACACTATGT
ATCTGAAAAACTTGTTCTCTGAAGAGAACCTCAAGGACATCGTCCTGAAGCTTAACG
GGGAGGCGGAGATCTTCTTTAGAAAGTCCTCTATCAAAAATCCCATTATCCATAAAA
AGGGCTCTATACTCGTTAATAGGACATATGAAGCGGAGGAAAAAGATCAATTTGGG
AACATCCAGATCGTCCGGAAAAATATACCTGAGAATATCTATCAAGAGCTGTACAA
GTATTTTAATGATAAGTCAGACAAAGAGCTCAGTGATGAGGCGGCAAAGCTCAAGA
ACGTGGTGGGGCATCATGAAGCTGCGACGAACATTGTCAAAGATTATAGATACACT
TACGATAAATACTTCCTCCACATGCCGATAACGATTAACTTCAAAGCCAATAAGACG
GGGTTTATAAATGATCGGATCCTTCAGTACATTGCGAAAGAGAAAGACCTCCATGTG
ATCGGAATTGACCGAGGAGAAAGGAATCTGATTTACGTGTCCGTGATTGATACTTGC
GGGAATATAGTCGAGCAAAAGAGTTTCAACATAGTCAACGGGTATGACTATCAGAT
AAAGCTCAAACAGCAGGAAGGTGCGAGGCAAATTGCGCGCAAAGAGTGGAAGGAG
ATAGGCAAGATTAAAGAAATCAAGGAAGGTTATCTCAGCTTGGTGATCCATGAAAT
ATCTAAGATGGTTATAAAGTACAATGCCATAATAGCCATGGAGGATCTTTCCTACGG
GTTTAAGAAGGGCCGATTTAAAGTGGAGCGACAAGTTTACCAGAAGTTCGAAACCA
TGTTGATTAACAAACTTAACTATTTGGTGTTCAAGGATATAAGTATAACCGAAAACG
GCGGTTTGCTTAAGGGTTATCAGCTCACGTATATTCCTGATAAACTTAAAAACGTTG
GACACCAGTGTGGATGTATCTTCTACGTGCCAGCCGCTTACACTAGTAAGATAGATC
CTACCACGGGGTTTGTGAATATTTTTAAGTTTAAAGACTTGACAGTCGACGCCAAAA
GGGAATTTATAAAAAAGTTTGATTCTATCCGCTACGATAGTGAAAAAAATCTCTTTT
GCTTTACTTTCGACTATAACAACTTCATTACGCAGAACACTGTCATGAGTAAGTCCA
GCTGGAGCGTCTACACATATGGCGTCCGAATTAAACGACGATTTGTAAACGGGCGG
TTTTCAAACGAATCTGACACGATAGACATTACCAAGGATATGGAGAAGACACTTGA
GATGACCGACATAAACTGGCGGGACGGTCACGATCTTCGGCAGGACATAATTGATT
ACGAAATCGTCCAGCATATATTCGAAATATTTCGACTTACAGTGCAAATGCGGAACA
GTCTCTCTGAACTGGAAGATCGCGATTATGACCGGTTGATTTCTCCGGTCCTCAATG
AAAATAACATATTTTATGATAGTGCTAAGGCAGGTGATGCGTTGCCAAAGGATGCA
GACGCTAATGGTGCCTATTGTATCGCGCTCAAGGGATTGTACGAGATAAAGCAAATT
ACGGAGAACTGGAAGGAGGATGGTAAGTTTAGCCGAGACAAGTTGAAGATTAGCAA
TAAAGACTGGTTTGATTTTATCCAAAACAAGAGGTACCTGAAACGTCCGGCAGCGA
CCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAG
CCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGG
GCTAA
SEQ ID NO: 103
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAACGGAACTA
ATAACTTTCAAAATTTCATAGGTATTTCAAGCTTGCAGAAGACCCTGAGGAATGCCC
TGATTCCAACCGAGACAACGCAGCAGTTCATAGTCAAAAATGGCATTATTAAGGAA
GATGAGCTGCGGGGGGAAAACCGACAGATACTCAAGGATATTATGGACGACTATTA
CCGGGGATTTATCTCAGAAACGCTGAGCAGTATTGATGACATCGATTGGACCAGTCT
TTTCGAGAAAATGGAAATTCAACTTAAGAATGGTGACAATAAAGACACTCTCATAA
AGGAGCAAACTGAATACCGAAAAGCCATACACAAAAAGTTTGCCAACGATGACCGC
TTTAAAAACATGTTTTCAGCTAAGCTCATTAGCGACATTCTCCCCGAGTTTGTGATTC
ATAACAATAACTATAGCGCATCCGAGAAGGAGGAAAAAACCCAAGTTATCAAATTG
TTCAGTAGATTCGCTACGAGCTTTAAAGATTACTTTAAAAACCGGGCTAACTGCTTC
AGTGCAGACGATATCAGCTCCTCATCCTGTCATCGCATCGTCAATGATAATGCTGAG
ATCTTCTTTTCTAATGCACTGGTTTACCGCAGGATAGTTAAGTCTCTTAGTAACGACG
ACATCAACAAGATATCAGGAGATATGAAGGATTCCCTTAAAGAAATGAGTCTCGAG
GAGATATATTCTTATGAAAAATACGGCGAATTTATTACCCAAGAGGGCATTAGTTTC
TATAATGACATATGCGGAAAAGTTAATAGTTTTATGAATCTCTATTGTCAGAAGAAT
AAGGAGAATAAGAACCTCTACAAATTGCAGAAGTTGCACAAGCAAATTCTGTGTAT
CGCGGACACCTCTTACGAGGTCCCATATAAGTTCGAGAGTGATGAAGAAGTATACC
AGAGCGTTAATGGGTTCCTGGACAACATCTCAAGTAAACACATAGTCGAAAGGCTC
CGAAAGATCGGTGATAACTATAACGGATATAATTTGGATAAAATTTATATAGTTAGC
AAATTTTACGAGAGCGTCAGTCAGAAGACCTACCGGGACTGGGAGACCATAAACAC
AGCGCTGGAAATACATTATAACAACATACTGCCTGGGAACGGTAAGTCAAAGGCAG
ACAAGGTTAAAAAGGCTGTGAAGAATGACCTGCAAAAATCAATTACAGAAATAAAT
GAGTTGGTAAGTAATTACAAACTTTGCAGCGATGATAATATAAAGGCAGAGACGTA
CATACATGAAATATCTCATATCCTCAACAATTTCGAAGCCCAAGAACTGAAGTACAA
CCCGGAAATTCATCTTGTAGAGTCTGAGTTGAAGGCCTCCGAATTGAAAAACGTTCT
TGACGTAATTATGAATGCCTTCCACTGGTGCTCAGTATTCATGACGGAAGAGCTCGT
GGATAAAGACAACAATTTTTACGCTGAACTGGAAGAAATATATGACGAGATTTACC
CCGTAATTTCACTCTACAACTTGGTACGAAATTACGTTACCCAAAAGCCATACTCAA
CAAAAAAAATTAAACTGAACTTCGGGATACCCACCCTCGCAGATGGATGGTCAAAG
TCCAAAGAGTACAGTAACAATGCAATTATCCTGATGCGAGACAACCTTTATTACCTC
GGGATTTTCAACGCTAAAAATAAACCTGATAAAAAAATAATTGAGGGTAATACCTC
TGAAAACAAGGGGGATTATAAAAAGATGATATACAATCTGCTGCCTGGCCCGAACA
AAATGATTCCTAAAGTCTTCTTGTCTTCCAAGACTGGAGTCGAAACCTACAAGCCAA
GTGCTTATATACTCGAAGGGTACAAACAAAATAAGCACATAAAATCCAGCAAGGAT
TTTGATATTACATTCTGCCACGATTTGATTGATTATTTTAAGAACTGTATAGCCATCC
ACCCAGAATGGAAGAATTTTGGTTTTGATTTTAGCGATACCTCAACATATGAGGATA
TCTCTGGCTTTTACCGCGAGGTAGAACTGCAAGGTTATAAGATCGATTGGACTTATA
TTTCTGAAAAGGACATAGATCTCCTGCAAGAGAAAGGGCAACTTTATTTGTTTCAAA
TATACAACAAAGATTTTAGTAAGAAGAGTACTGGCAATGATAACCTTCACACTATGT
ATCTGAAGAACCTTTTTTCTGAGGAGAACTTGAAGGACATAGTCCTTAAACTCAATG
GGGAAGCTGAAATATTCTTTCGCAAAAGCTCCATTAAAAACCCGATCATTCATAAAA
AGGGTTCCATCTTGGTAAACCGCACATACGAGGCGGAAGAAAAAGATCAGTTCGGA
AATATCCAGATCGTAAGGAAGAATATCCCCGAAAATATATACCAAGAGCTTTACAA
ATATTTTAACGATAAGTCAGACAAGGAACTGTCAGACGAAGCAGCCAAGTTGAAGA
ATGTCGTAGGGCACCACGAAGCAGCTACAAACATAGTTAAAGATTATCGGTACACC
TACGATAAATATTTCCTGCATATGCCAATAACCATAAACTTCAAAGCCAACAAAACA
GGGTTCATCAATGACCGAATACTTCAGTATATAGCCAAGGAAAAAGACCTGCATGTT
ATAGGAATAGATAGAGGTGAGCGCAACTTGATATATGTCAGCGTGATAGACACCTG
CGGAAATATCGTCGAGCAAAAAAGTTTCAACATTGTTAATGGCTACGATTACCAAAT
TAAATTGAAGCAGCAAGAGGGGGCTCGGCAAATCGCGCGAAAGGAATGGAAAGAA
ATCGGGAAGATTAAAGAAATTAAAGAGGGCTACCTGTCTCTTGTAATTCACGAAAT
ATCTAAGATGGTCATCAAGTATAATGCCATTATTGCGATGGAAGATCTGTCCTACGG
ATTTAAGAAAGGCAGGTTTAAAGTCGAAAGGCAGGTGTACCAGAAATTCGAGACCA
TGCTGATTAATAAGCTCAACTATCTCGTATTTAAGGATATTTCTATAACTGAAAATG
GAGGGCTTCTCAAAGGATATCAACTCACATACATACCTGATAAGCTGAAGAACGTA
GGCCACCAGTGTGGATGCATATTCTATGTACCAGCTGCATACACAAGCAAGATCGAT
CCAACTACTGGGTTTGTCAATATCTTCAAATTTAAGGACTTGACGGTCGATGCCAAA
CGGGAGTTCATCAAAAAGTTTGATAGTATTCGATATGATAGTGAGAAGAACTTGTTT
TGCTTCACATTTGACTACAACAATTTCATAACGCAAAATACGGTTATGTCTAAATCC
TCATGGAGCGTCTACACTTACGGAGTGAGGATAAAGCGGCGCTTCGTAAATGGCAG
GTTTAGCAATGAATCCGACACGATTGACATAACCAAGGATATGGAGAAAACCCTCG
AGATGACCGATATAAATTGGCGGGATGGACACGATCTGCGACAAGACATAATCGAT
TATGAAATCGTGCAGCACATATTTGAGATATTCAGGCTTACGGTCCAAATGAGAAAT
TCCCTTTCCGAACTTGAAGACCGCGATTACGACCGACTGATAAGCCCCGTTCTGAAC
GAAAATAACATCTTCTACGACAGCGCTAAAGCGGGAGACGCGCTGCCGAAAGATGC
GGACGCAAATGGAGCCTATTGTATCGCCTTGAAAGGGTTGTACGAGATCAAACAGA
TAACCGAGAATTGGAAGGAGGATGGGAAGTTTAGTCGAGACAAACTTAAAATAAGC
AACAAGGACTGGTTCGACTTTATTCAAAACAAACGATATCTCAAACGTCCGGCAGC
GACCAAAAAAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGC
AGCCCGAAAAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCC
GGGCTAA
SEQ ID NO: 104
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAATGGTACTAA
CAATTTTCAAAACTTTATCGGCATCTCTTCACTTCAGAAAACTCTTCGGAACGCCCTT
ATACCGACGGAGACAACGCAGCAGTTTATAGTTAAAAACGGGATCATTAAAGAAGA
TGAACTCAGAGGGGAAAACAGGCAAATATTGAAGGACATTATGGACGATTACTACC
GGGGGTTTATTTCAGAGACCCTTTCATCTATTGATGACATAGATTGGACCTCCCTTTT
CGAGAAAATGGAGATACAATTGAAAAACGGCGACAATAAAGATACACTTATCAAGG
AACAAACTGAGTATCGCAAGGCGATTCACAAGAAGTTTGCGAATGACGATCGCTTT
AAGAATATGTTTTCTGCGAAGCTCATAAGTGACATTCTGCCTGAATTTGTCATTCATA
ACAACAATTATTCTGCTAGCGAAAAAGAGGAAAAAACTCAAGTCATTAAGCTTTTTA
GCAGGTTCGCTACTAGTTTTAAAGACTATTTTAAGAACCGGGCGAATTGCTTTAGCG
CTGACGACATATCATCCTCATCCTGTCATCGCATAGTCAATGATAATGCAGAAATAT
TCTTTTCTAATGCGCTCGTGTATCGGAGAATAGTGAAAAGCCTCTCTAACGATGACA
TTAACAAAATAAGCGGCGATATGAAGGATAGTCTGAAGGAAATGTCCCTCGAAGAA
ATATACTCATACGAGAAGTACGGAGAATTTATCACCCAGGAAGGAATTAGTTTTTAC
AACGACATCTGTGGTAAGGTTAACTCTTTTATGAATCTGTATTGTCAAAAGAATAAA
GAAAATAAAAATCTTTATAAGCTCCAAAAGCTTCACAAACAAATCTTGTGCATTGCG
GATACGTCATACGAAGTACCTTACAAATTTGAAAGCGACGAAGAGGTGTATCAGTC
AGTGAATGGGTTCCTTGACAATATTTCTAGCAAACATATTGTGGAGCGACTTCGAAA
GATCGGTGATAATTACAATGGCTATAATTTGGATAAAATTTACATAGTTAGTAAGTT
TTATGAATCCGTCTCACAAAAGACGTACCGAGATTGGGAGACCATCAACACTGCTCT
GGAGATTCATTACAATAATATATTGCCTGGGAATGGGAAGTCAAAGGCCGACAAGG
TTAAAAAAGCCGTAAAAAACGATCTTCAAAAGTCCATTACCGAGATAAATGAACTT
GTATCCAACTATAAGTTGTGCTCTGACGATAATATTAAAGCAGAAACGTATATCCAC
GAAATAAGTCACATCCTGAACAACTTCGAAGCTCAAGAGCTCAAGTATAATCCTGA
AATTCATCTCGTCGAAAGCGAGCTGAAAGCATCCGAGTTGAAGAATGTGCTTGATGT
GATCATGAACGCATTCCATTGGTGCAGTGTGTTCATGACCGAAGAACTTGTAGACAA
AGACAACAACTTCTACGCTGAATTGGAAGAGATTTACGATGAAATTTACCCCGTGAT
ATCCCTCTATAATCTGGTAAGAAATTACGTCACGCAAAAACCATACAGTACCAAGA
AAATAAAGCTCAACTTTGGTATTCCGACGTTGGCAGATGGGTGGAGTAAGAGCAAG
GAGTATTCTAACAATGCAATCATCCTCATGCGCGACAATTTGTATTATCTGGGGATC
TTCAACGCGAAAAATAAGCCCGACAAAAAGATAATAGAAGGCAATACGTCCGAGA
ACAAAGGGGACTATAAGAAAATGATTTATAACCTTCTTCCAGGACCCAACAAGATG
ATCCCAAAGGTTTTCTTGAGTTCAAAAACCGGCGTAGAAACTTATAAACCGTCCGCC
TACATTCTGGAAGGGTACAAGCAAAACAAGCACATTAAGTCATCTAAGGATTTCGA
CATTACTTTTTGTCATGATTTGATAGACTACTTCAAAAATTGTATAGCGATACATCCG
GAATGGAAAAATTTTGGGTTCGATTTTTCCGACACAAGTACTTATGAAGACATCTCA
GGGTTTTATAGGGAAGTTGAACTGCAAGGTTACAAAATAGACTGGACTTATATTAGT
GAGAAGGACATTGATTTGCTCCAGGAAAAGGGTCAATTGTATCTGTTCCAGATATAT
AACAAGGATTTCTCTAAAAAATCTACAGGTAACGACAATCTCCACACGATGTACCTC
AAGAATCTCTTCAGCGAAGAGAATTTGAAGGATATCGTACTTAAGCTCAATGGAGA
AGCGGAAATATTCTTCAGAAAGTCCAGCATTAAGAATCCTATAATTCACAAGAAAG
GGTCAATTCTCGTAAACCGGACTTATGAGGCCGAAGAAAAAGATCAGTTTGGTAAC
ATTCAGATTGTACGGAAAAACATTCCCGAGAACATCTATCAAGAACTGTATAAATAC
TTTAATGATAAATCCGACAAGGAACTTTCTGACGAGGCTGCAAAATTGAAGAACGT
AGTGGGACACCATGAGGCCGCAACCAATATAGTAAAGGATTACAGATACACTTATG
ATAAGTATTTCCTCCATATGCCGATCACGATTAATTTCAAGGCGAATAAAACCGGCT
TCATTAACGATCGCATTTTGCAATATATTGCGAAGGAAAAGGATTTGCACGTGATAG
GTATAGACCGGGGTGAACGAAACTTGATTTACGTCTCTGTGATCGACACATGCGGAA
ATATAGTTGAACAGAAGTCCTTTAATATTGTGAATGGTTACGACTACCAGATAAAAT
TGAAGCAACAGGAGGGCGCAAGACAGATAGCTCGCAAAGAGTGGAAGGAAATCGG
CAAGATCAAAGAAATAAAGGAGGGTTATCTTTCCCTGGTAATTCATGAAATTAGCA
AGATGGTTATTAAGTATAATGCTATAATAGCTATGGAGGACCTTTCCTATGGGTTCA
AGAAAGGTCGCTTCAAAGTGGAGCGACAAGTGTATCAAAAGTTCGAGACTATGTTG
ATAAATAAATTGAATTATTTGGTTTTTAAAGACATTTCAATAACTGAGAACGGGGGT
CTCTTGAAGGGGTACCAATTGACTTATATTCCGGACAAGTTGAAGAATGTCGGACAC
CAGTGTGGTTGCATTTTCTACGTGCCTGCCGCTTACACCTCAAAAATCGATCCGACC
ACTGGTTTTGTAAATATATTTAAATTCAAAGATCTCACCGTTGATGCCAAACGGGAG
TTTATCAAAAAATTCGATTCCATTCGCTACGACTCTGAGAAAAACCTTTTTTGTTTCA
CGTTCGATTATAACAACTTTATAACCCAAAATACTGTAATGTCCAAGTCAAGTTGGT
CTGTCTATACTTACGGAGTAAGGATCAAGCGCCGCTTCGTTAATGGGAGATTCTCAA
ACGAGTCTGATACCATAGACATAACTAAAGACATGGAAAAAACCCTGGAAATGACG
GACATCAATTGGCGAGACGGGCATGATCTTCGACAGGACATAATAGATTACGAAAT
TGTTCAACACATTTTCGAGATATTTCGACTTACGGTTCAGATGAGGAATTCCCTTTCC
GAATTGGAAGACCGGGATTATGATCGACTTATATCTCCCGTGCTCAATGAAAACAAT
ATTTTTTATGATTCAGCGAAAGCTGGGGACGCGCTGCCAAAAGATGCCGATGCCAAT
GGAGCATACTGTATCGCCCTGAAGGGTTTGTATGAGATTAAGCAAATTACTGAAAAC
TGGAAGGAAGATGGCAAGTTTTCTAGAGATAAGCTTAAGATTAGCAATAAGGACTG
GTTTGACTTCATTCAAAATAAAAGGTATCTTAAACGTCCGGCAGCGACCAAAAAAG
CCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAAAAA
GAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 105
CCAGCGGCTAAAAAAAAGAAACTGGATGGCAGCGTGGATATGAATAATGGAACAA
ATAATTTTCAAAATTTTATTGGTATCAGTTCATTGCAAAAGACTTTGAGAAATGCTTT
GATCCCGACTGAGACCACACAGCAGTTCATCGTCAAAAATGGCATAATCAAGGAAG
ACGAACTTAGGGGTGAGAATAGACAAATATTGAAGGACATCATGGATGACTATTAT
AGGGGGTTCATTTCCGAAACGCTCAGTAGTATTGATGACATTGACTGGACTAGTCTT
TTCGAGAAAATGGAAATTCAGCTTAAGAACGGGGACAATAAAGACACGCTGATCAA
GGAGCAAACGGAATATAGGAAGGCGATCCATAAAAAATTCGCGAATGATGATCGGT
TTAAAAACATGTTTAGTGCCAAGTTGATCAGCGACATACTGCCCGAATTCGTGATCC
ACAACAATAATTACAGCGCCTCCGAAAAGGAGGAAAAAACTCAGGTCATTAAATTG
TTTAGCCGATTCGCAACGAGTTTCAAAGATTATTTTAAGAACCGGGCCAACTGTTTT
TCAGCGGATGATATTAGCTCCAGCAGCTGCCATCGCATAGTAAATGATAACGCTGAA
ATCTTTTTTAGCAACGCACTTGTCTACCGGAGGATTGTAAAATCACTGTCAAATGAT
GACATTAACAAAATATCTGGAGATATGAAGGACTCACTCAAAGAAATGAGCCTGGA
AGAAATATATTCATACGAAAAATACGGGGAGTTTATTACCCAGGAAGGTATCAGTTT
TTATAATGATATATGTGGAAAAGTTAATTCATTTATGAATCTTTACTGTCAAAAAAA
TAAGGAGAACAAGAATTTGTACAAGCTCCAAAAACTTCATAAACAGATTCTGTGCA
TCGCAGACACAAGTTATGAGGTACCGTACAAATTTGAGAGCGACGAAGAAGTTTAT
CAGAGTGTGAATGGTTTCCTGGACAATATCTCTTCTAAACACATTGTTGAGAGGCTT
AGGAAGATCGGTGATAATTATAACGGCTATAATCTGGACAAAATTTATATTGTATCA
AAGTTTTATGAATCAGTCTCTCAAAAGACGTATCGGGATTGGGAAACAATTAACACG
GCTCTGGAGATCCACTACAATAACATTCTGCCCGGCAACGGGAAGAGCAAAGCTGA
TAAGGTCAAGAAGGCAGTCAAGAACGACCTTCAGAAGAGCATAACAGAAATTAACG
AATTGGTCAGTAACTACAAACTGTGTAGTGATGACAACATAAAAGCCGAAACATAC
ATCCATGAAATAAGCCATATCCTGAATAACTTCGAAGCCCAAGAACTTAAATACAAT
CCCGAGATTCATCTTGTCGAATCAGAACTCAAGGCGTCCGAGCTCAAAAATGTCCTT
GACGTGATAATGAATGCCTTCCACTGGTGCAGCGTATTCATGACGGAGGAGTTGGTA
GATAAAGACAACAACTTTTATGCCGAATTGGAAGAGATTTATGATGAGATTTACCCC
GTTATTTCTCTGTACAACTTGGTTCGAAACTACGTAACACAAAAACCATACTCAACC
AAAAAGATCAAACTCAATTTTGGCATACCTACATTGGCTGATGGTTGGTCCAAGTCA
AAGGAATATAGCAATAATGCAATAATTCTCATGCGAGATAACTTGTATTATTTGGGG
ATCTTTAACGCTAAGAACAAACCAGATAAAAAGATAATCGAGGGGAACACAAGTGA
GAACAAGGGTGATTACAAAAAAATGATTTACAATCTGCTTCCTGGGCCTAACAAAA
TGATTCCGAAGGTGTTTCTTAGCTCTAAAACTGGAGTGGAGACGTATAAGCCTTCCG
CGTACATTCTCGAAGGCTACAAGCAAAATAAGCATATCAAGTCCAGTAAGGACTTC
GACATCACTTTTTGCCACGATCTCATCGATTACTTTAAGAACTGTATCGCAATACACC
CCGAGTGGAAAAACTTTGGTTTTGATTTTTCAGACACTAGTACCTACGAGGACATTT
CCGGCTTCTATCGAGAAGTCGAACTCCAGGGCTACAAAATCGATTGGACGTACATTT
CTGAGAAGGACATCGACTTGCTCCAAGAGAAAGGTCAACTTTACCTCTTCCAAATTT
ACAATAAAGACTTTTCAAAGAAGAGCACCGGTAATGACAACTTGCATACCATGTAT
CTGAAGAACCTGTTTTCTGAGGAGAACCTCAAGGATATTGTATTGAAGTTGAATGGC
GAAGCAGAAATATTTTTCCGAAAGTCATCTATCAAGAACCCCATTATACACAAAAA
AGGCTCTATCCTGGTGAACCGGACTTACGAGGCAGAGGAGAAGGATCAATTCGGAA
ACATACAGATAGTCCGCAAAAACATCCCTGAGAATATCTATCAGGAACTCTATAAGT
ACTTCAATGATAAATCAGACAAGGAGCTTAGCGACGAAGCAGCTAAACTTAAAAAC
GTGGTTGGCCATCACGAGGCCGCTACCAACATAGTCAAAGACTACCGCTATACTTAT
GACAAGTACTTTTTGCACATGCCCATAACAATTAATTTCAAAGCTAACAAAACAGGG
TTTATAAATGACAGAATCCTCCAATACATCGCCAAAGAGAAGGACCTCCATGTAATC
GGGATTGATAGAGGCGAACGGAACTTGATTTACGTTAGTGTCATTGATACCTGTGGT
AACATTGTCGAACAAAAGTCATTCAACATAGTCAATGGATATGATTATCAGATAAA
ACTCAAGCAACAAGAAGGCGCGAGGCAGATTGCCAGGAAGGAATGGAAAGAAATC
GGGAAGATCAAGGAGATCAAGGAGGGTTACCTGTCCTTGGTGATACACGAGATTTC
AAAAATGGTTATAAAATACAATGCCATTATCGCGATGGAGGATTTGTCTTATGGATT
TAAGAAGGGGAGGTTCAAAGTCGAACGACAAGTCTATCAGAAGTTTGAAACAATGC
TCATTAACAAGCTCAATTACCTTGTTTTCAAGGATATAAGCATCACTGAAAACGGCG
GACTCCTTAAGGGATATCAGCTGACTTATATCCCCGACAAGCTCAAGAACGTAGGGC
ACCAATGCGGATGCATCTTTTACGTGCCTGCAGCATATACTTCAAAAATTGATCCGA
CTACTGGCTTTGTTAACATTTTCAAGTTCAAGGATCTGACGGTAGACGCTAAGAGAG
AATTCATAAAAAAGTTTGACAGCATCAGGTACGATAGTGAAAAGAACCTTTTTTGTT
TTACCTTTGACTACAATAATTTTATTACGCAAAATACAGTTATGAGCAAATCAAGTT
GGAGCGTTTACACATATGGCGTTCGGATCAAGCGCAGATTCGTCAATGGTCGCTTCT
CAAATGAGAGCGATACAATCGATATAACGAAGGATATGGAGAAGACGCTTGAGATG
ACAGATATCAACTGGCGGGACGGACATGACCTTAGACAAGACATAATCGATTACGA
AATAGTACAGCATATCTTTGAGATTTTTAGGCTTACAGTTCAGATGCGGAACTCTCTT
TCCGAACTGGAGGACCGGGATTATGATCGGTTGATCTCCCCAGTACTGAACGAAAAT
AATATCTTTTACGATAGCGCGAAGGCTGGTGATGCACTCCCAAAAGACGCTGATGCG
AACGGAGCTTATTGCATAGCCCTTAAAGGGCTTTACGAGATTAAACAAATAACAGA
AAATTGGAAGGAAGATGGCAAATTTTCCCGCGACAAGTTGAAGATTAGTAACAAAG
ACTGGTTCGACTTCATTCAGAATAAACGCTACCTCAAACGTCCGGCAGCGACCAAAA
AAGCCGGCCAGGCGAAGAAAAAAAAAGCGTCAGGTAGCGGCGCAGGCAGCCCGAA
AAAGAAACGTAAAGTCGAGGATCCGAAAAAGAAACGTAAGGTTATTCCGGGCTAA
SEQ ID NO: 113
ATGGGCCATCATCATCATCATCATAGCAGCGGCGTGGATCTGGGCACCGAAAACCT
GTATTTTCAGTCCATGAGCCGCCGCCGCAAAGCGAACCCGACCAAACTGAGCGAAA
ACGCGAAAAAACTGGCGAAAGAAGTGGAAAACGCAAGCGGCAGCGGCGCGGGCAG
CAAACGACCGGCGGCGACCAAAAAAGCGGGCCAAGCGAAGAAAAAGAAAGCAAGC
GGCAGCGGCGCGGGCAGCCCGGCGGCAAAAAAAAAAAAACTGGACGGCAGCGTGG
ATGCAAGCGGCAGCGGCGCGGGCAGCCCCAAAAAAAAACGCAAAGTTGAAGATGC
AAGCGGCAGCGGCGCGGGCAGCCCGAAAAAAAAACGTAAAGTGGCAAGCGGCAGC
GGCGCGGGCAGCATGAACAACGGCACCAACAACTTTCAGAACTTTATTGGCATTAG
CAGCCTGCAGAAAACCCTGCGCAACGCGCTGATTCCGACCGAAACCACGCAGCAGT
TTATTGTGAAAAACGGCATTATTAAAGAAGATGAACTGCGCGGCGAAAACCGTCAG
ATTCTGAAGGACATTATGGATGATTATTATCGCGGCTTTATTAGCGAAACCCTGAGC
AGCATTGATGATATAGACTGGACGAGCCTGTTTGAAAAAATGGAAATTCAGCTGAA
AAACGGCGATAACAAAGATACCCTGATTAAAGAACAGACCGAATATCGCAAAGCGA
TTCATAAGAAGTTTGCGAACGATGATCGCTTTAAAAACATGTTTAGCGCGAAACTGA
TTAGCGATATTCTGCCGGAATTTGTGATTCATAACAACAACTATAGCGCGAGCGAAA
AGGAAGAAAAAACCCAAGTGATTAAACTGTTTAGCCGCTTTGCGACGAGCTTTAAA
GATTATTTTAAAAATCGCGCGAACTGCTTTAGCGCGGATGATATTAGCAGCAGCAGC
TGCCATCGCATTGTGAACGATAACGCGGAGATCTTTTTTAGCAATGCGCTGGTGTAT
CGCCGCATTGTGAAAAGCCTGAGCAACGATGATATTAACAAAATTAGCGGCGATAT
GAAAGATAGCCTGAAAGAAATGAGCCTGGAAGAAATATATAGCTATGAAAAATATG
GGGAATTTATTACACAAGAGGGCATTAGCTTTTATAACGATATTTGCGGCAAAGTGA
ACAGCTTTATGAACCTGTATTGTCAGAAAAACAAAGAAAACAAAAACCTGTATAAA
CTGCAGAAACTGCATAAACAGATTCTGTGCATTGCGGATACGAGCTATGAAGTGCC
GTATAAATTTGAAAGCGATGAAGAAGTGTATCAGAGCGTGAACGGCTTTCTGGATA
ACATTAGCAGCAAACATATTGTGGAACGCCTGCGCAAAATTGGCGATAACTATAAC
GGCTATAACCTGGATAAAATTTATATTGTGAGCAAATTTTATGAAAGCGTGAGTCAG
AAAACCTATCGCGATTGGGAAACCATTAACACCGCGCTGGAAATTCATTATAACAA
CATTCTGCCGGGCAACGGCAAAAGTAAAGCGGATAAAGTGAAAAAAGCGGTGAAA
AACGATCTGCAGAAAAGCATTACGGAAATTAACGAACTGGTGAGCAACTATAAACT
GTGCAGCGATGATAACATTAAAGCGGAAACCTATATTCACGAGATCAGTCATATTCT
GAACAACTTTGAAGCGCAAGAACTGAAATATAACCCGGAAATTCATCTGGTGGAAT
CAGAACTGAAGGCGAGCGAACTTAAGAATGTGCTAGATGTGATTATGAACGCGTTT
CATTGGTGCAGCGTGTTTATGACCGAAGAACTGGTGGATAAAGATAACAACTTTTAT
GCGGAACTGGAAGAAATCTACGACGAAATTTATCCGGTGATTAGCCTGTATAACCTG
GTGCGCAACTATGTGACGCAGAAACCGTATAGCACCAAAAAAATTAAACTGAACTT
TGGCATTCCGACCCTGGCGGATGGCTGGAGCAAGAGCAAAGAGTATAGCAACAACG
CTATTATCCTAATGCGCGATAACCTGTATTATCTGGGCATTTTTAACGCGAAAAACA
AACCGGATAAAAAAATTATTGAAGGCAACACGAGCGAAAACAAAGGCGATTATAA
AAAAATGATTTATAACCTGCTGCCGGGCCCGAACAAAATGATTCCGAAAGTGTTTCT
GAGCAGCAAAACCGGCGTGGAAACCTATAAACCGAGCGCGTATATTCTGGAAGGCT
ATAAACAGAACAAACATATTAAAAGCAGCAAAGATTTTGATATTACCTTTTGCCATG
ATCTGATTGACTACTTTAAGAACTGTATAGCGATTCATCCGGAATGGAAAAACTTTG
GCTTTGATTTTAGCGATACGAGCACCTATGAAGACATTAGCGGCTTTTATCGCGAAG
TGGAACTGCAAGGCTATAAAATTGATTGGACCTATATTAGCGAAAAAGATATTGATC
TGCTGCAAGAAAAAGGTCAGCTGTATCTGTTTCAGATTTATAACAAAGATTTTAGCA
AAAAAAGCACCGGCAACGATAACCTGCATACCATGTATCTGAAAAATCTGTTTTCTG
AAGAAAACCTAAAAGATATTGTCCTGAAACTGAACGGCGAAGCCGAAATTTTTTTTC
GCAAGAGCAGCATTAAAAACCCGATTATTCACAAAAAAGGTAGCATTCTGGTGAAC
CGCACATACGAAGCTGAGGAAAAGGATCAGTTTGGCAACATTCAGATTGTGCGCAA
AAACATTCCGGAAAACATCTACCAAGAACTGTACAAATATTTTAACGATAAAAGCG
ATAAAGAACTGAGCGACGAGGCTGCGAAGCTGAAGAATGTCGTGGGCCATCATGAA
GCGGCGACTAACATTGTCAAAGATTATCGCTATACCTATGATAAATATTTTCTGCAT
ATGCCGATTACCATTAACTTTAAAGCGAACAAAACCGGCTTTATTAACGATCGCATT
CTGCAGTATATTGCGAAGGAAAAGGATCTGCACGTGATTGGCATTGATCGCGGCGA
ACGCAACCTGATTTATGTGAGCGTGATTGATACCTGCGGCAACATTGTGGAACAGAA
AAGCTTTAACATCGTGAACGGCTATGATTATCAGATTAAACTGAAACAGCAAGAAG
GCGCGCGTCAGATTGCGCGCAAAGAATGGAAAGAAATTGGCAAAATTAAAGAAATT
AAAGAAGGCTATCTGAGCCTGGTGATTCATGAAATCAGCAAGATGGTGATTAAATA
TAATGCCATTATTGCGATGGAAGATCTGAGCTATGGCTTTAAAAAAGGCCGCTTTAA
AGTGGAACGCCAAGTGTATCAGAAATTTGAAACCATGCTGATTAACAAACTGAACT
ATCTGGTGTTTAAAGATATTAGTATTACTGAAAATGGCGGCCTGCTGAAAGGCTATC
AGCTGACCTATATTCCGGACAAGCTGAAGAATGTGGGCCATCAGTGCGGCTGCATTT
TTTATGTGCCGGCGGCGTATACGAGCAAAATTGATCCGACCACCGGCTTTGTGAACA
TTTTTAAATTTAAAGATCTGACCGTGGATGCGAAACGGGAATTCATAAAAAAATTTG
ATAGCATTCGCTATGATAGCGAAAAGAATCTGTTTTGCTTCACCTTTGATTATAACA
ACTTTATAACGCAGAACACCGTGATGAGCAAAAGCAGCTGGAGCGTGTATACCTAT
GGCGTGCGCATTAAACGCCGCTTTGTGAACGGCCGCTTTAGCAACGAAAGCGATAC
CATTGATATTACCAAAGATATGGAAAAAACCCTGGAAATGACCGATATTAACTGGC
GCGATGGCCATGATCTGCGCCAAGATATTATTGATTATGAAATTGTGCAGCATATTT
TTGAAATTTTTCGCCTGACCGTGCAGATGCGCAACAGCCTGAGCGAACTGGAAGATC
GCGATTATGATCGCCTGATTAGCCCGGTGCTGAACGAAAACAACATTTTTTATGATA
GCGCGAAAGCGGGCGATGCGCTGCCGAAAGATGCGGATGCGAACGGCGCGTATTGC
ATTGCGCTGAAAGGCCTGTATGAAATTAAACAGATTACGGAAAACTGGAAAGAAGA
TGGCAAATTTAGCCGCGACAAGCTGAAAATTAGCAACAAAGATTGGTTTGATTTTAT
TCAGAACAAACGCTATCTGTA
In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least 50% identity to SEQ ID NO:2. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to amino acid sequence of SEQ ID NO:2. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least 50% identity to SEQ ID NO: 3. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical, to amino acid sequence of SEQ ID NO: 3. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least 50% identity to SEQ ID NO: 4. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to amino acid sequences of SEQ ID NO: 4. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least 50% identity to any one of SEQ ID NOs: 109-112. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to amino acid sequence of any one of SEQ ID NOs: 109-112. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least 50% identity to SEQ ID NO: 109. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to SEQ ID NO: 109. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least 50% identity to SEQ ID NO: 110. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to SEQ ID NO: 110. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least 50% identity to SEQ ID NO: 111. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to SEQ ID NO: 111. In certain embodiments, a nucleic acid-guided nuclease, e.g., Type V, preferably Type VA CRISPR nuclease polypeptide disclosed herein includes a polypeptide having an amino acid sequence of at least 50% identity to SEQ ID NO: 112. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to SEQ ID NO: 112.
Nuclear Localization Signals (NLSs) In certain embodiments, a composition, e.g., nuclease, disclosed herein includes one or more nuclear localization sequences (NLSs), such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more NLSs. In some embodiments, a composition, e.g., engineered nuclease comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more NLSs at or near the amino-terminus, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more NLSs at or near the carboxy-terminus, or a combination of these (e.g. one or more NLS at the amino-terminus and one or more NLS at the carboxy terminus). When more than one NLS is present, each may be selected independently of the others, such that a single NLS may be present in more than one copy and/or in combination with one or more other NLSs present in one or more copies. In certain embodiments the engineered nuclease comprises 4 NLSs.
Non-limiting examples of NLSs include an NLS sequence derived from: the NLS of the SV40 virus large T-antigen, having the amino acid sequence PKKKRKV (SEQ ID NO:5); the NLS from nucleoplasmin (e.g. the nucleoplasmin bipartite NLS with the sequence KRPAATKKAGQAKKKK (SEQ ID NO:6); the c-myc NLS having the amino acid sequence PAAKRVKLD SEQ ID NO:7) or RQRRNELKRSP (SEQ ID NO:8); the hRNPA1 M9 NLS having the sequence NQSSNFGPMKGGNFGGRSSGPYGGGGQYFAKPRNQGGY (SEQ ID NO:9); the sequence RMRIZFKNKGKDTAELRRRRVEVSVELRKAKKDEQILKRRNV (SEQ ID NO:10) of the IBB domain from importin-alpha; the sequences VSRKRPRP (SEQ ID NO:11) and PPKKARED (SEQ ID NO:12) of the myoma T protein; the sequence PQPKKKPL (SEQ ID NO:13) of human p53; the sequence SALI AP (SEQ ID NO:14) of mouse c-abl IV; the sequences DRLRR (SEQ ID NO:15) and PKQKKRK (SEQ ID NO:16) of the influenza virus NS1; the sequence RKLKKKIKKL (SEQ ID NO:17) of the Hepatitis virus delta antigen; the sequence REKKKFLKRR (SEQ ID NO:18) of the mouse Mx1 protein; the sequence KRKGDEVDGVDEVAKKKSKK (SEQ ID NO:19) of the human poly(ADP-ribose) polymerase; the sequence RKCLQAGMNLEARKTKK (SEQ ID NO:20) of the steroid hormone receptors (human) glucocorticoid; and EGL-13, MSRRRKANPTKLSENAKKLAKEVEN, SEQ ID NO: 107.
In certain embodiments, a nuclease provided herein comprises at least one myc-related NLS comprising the sequence PAAKKKKLD (SEQ ID NO:21); in certain embodiments the myc-related NLS is at the N-terminus of the nuclease. In certain embodiments, a nuclease provided herein comprises at least one nucleoplasmin NLS comprising the sequence KRPAATKKAGQAKKKK (SEQ ID NO:6); in certain embodiments the nucleoplasmin NLS is at the C-terminus of the nuclease. In certain embodiments a nuclease provided herein comprises at least one, or at least two, SV40 NLS sequences comprising the sequence PKKKRKV (SEQ ID NO:5); in certain embodiments the SV40 NLSs are at the C-terminus of the nuclease. In certain embodiments, a nuclease provided herein comprises 1 NLS at the N-terminus and 3 NLSs at the C-terminus, for example 1 myc-related NLS at the N-terminus and one nucleoplasmin NLS and two SV40 NLSs at the C-terminus. In certain embodiments, a nuclease provided herein comprises 1 myc-related NLS at the N-terminus with the sequence PAAKKKKLD (SEQ ID NO:21 and one nucleoplasmin NLS comprising the sequence KRPAATKKAGQAKKKK (SEQ ID NO:6) and two SV40 NLSs comprising the sequence PKKKRKV (SEQ ID NO:5) at the C-terminus.
In general, the one or more NLSs are of sufficient strength to drive accumulation of the nucleic acid-guided nuclease in a detectable amount in the nucleus of a eukaryotic cell. In general, strength of nuclear localization activity may derive from the number of NLSs, the particular NLS(s) used, or a combination of these factors. Detection of accumulation in the nucleus may be performed by any suitable technique. For example, a detectable marker may be fused to the nucleic acid-guided nuclease, such that location within a cell may be visualized, such as in combination with a means for detecting the location of the nucleus (e.g. a stain specific for the nucleus such as DAPI). Cell nuclei may also be isolated from cells, the contents of which may then be analyzed by any suitable process for detecting protein, such as immunohistochemistry, Western blot, or enzyme activity assay. Accumulation in the nucleus may also be determined indirectly, such as by an assay for the effect of the nucleic acid-guided nuclease complex formation (e.g. assay for DNA cleavage or mutation at the target sequence, or assay for altered gene expression activity affected by targetable nuclease complex formation and/or nucleic acid-guided nuclease activity), as compared to a control not exposed to the nucleic acid-guided nuclease or targetable nuclease complex, or exposed to a nucleic acid-guided nuclease lacking the one or more NLSs.
In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 4 and at least one myc-related NLS comprising the sequence PAAKKKKLD (SEQ ID NO:21); in certain embodiments the myc-related NLS is at the N-terminus of the nuclease. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 4 and at least one nucleoplasmin NLS comprising the sequence KRPAATKKAGQAKKKK (SEQ ID NO:6); in certain embodiments the nucleoplasmin NLS is at the C-terminus of the nuclease. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 4 and at least one, or at least two, SV40 NLS sequences comprising the sequence PKKKRKV (SEQ ID NO: 5); in certain embodiments the SV40 NLSs are at the C-terminus of the nuclease. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 4 and one NLS at the N-terminus and three NLSs at the C-terminus, for example 1 myc-related NLS at the N-terminus and one nucleoplasmin NLS and two SV40 NLSs at the C-terminus. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 4, and one myc-related NLS at the N-terminus with the sequence PAAKKKKLD (SEQ ID NO:21) and one nucleoplasmin NLS comprising the sequence KRPAATKKAGQAKKKK (SEQ ID NO:6) and two SV40 NLSs comprising the sequence PKKKRKV (SEQ ID NO:5) at the C-terminus. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 1, and one, two, or three NLS at the N-terminus and one, two, or three NLS at the C-terminus. In certain embodiments, a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 1, and one myc-related NLS at the N-terminus with the sequence PAAKKKKLD (SEQ ID NO:21) and one nucleoplasmin NLS comprising the sequence KRPAATKKAGQAKKKK (SEQ ID NO:6) and two SV40 NLSs comprising the sequence PKKKRKV (SEQ ID NO:5) at the C-terminus.
Purification Tags In certain embodiments, a nucleic acid-guided nuclease provided herein can comprise a tag, e.g., a purification tag, e.g. at the N-terminus. Exemplary tags include a poly-his tag, such as a Gly-6×His tag (SEQ ID NO: 421) or Gly-8×His tag (SEQ ID NO: 422), short epitope tags such as FLAG, hemagglutinin (HA), c-myc, T7, and Glu-Glu; maltose binding protein (mbp); N-terminal glutathione S-transferase (GST); calmodulin binding peptide (CBP). In certain embodiments, a nucleic acid-guided nuclease provided herein can comprise a poly-his tag, such as a Gly-6×His tag (SEQ ID NO: 421), e.g., at the N-terminus. These Gly-6×His tags (SEQ ID NO: 421) are applied for several reasons including: 1) a 6×His tag (SEQ ID NO: 423) can be used in protein purification to allow binding to the chromatographic columns for purification, and 2) the N-terminal glycine allows further, site-specific, chemical modifications that permit advanced protein engineering. Further, the Gly-6×His (SEQ ID NO: 421) is designed for easy removal, if desired, by digestion with Tobacco Etch Virus (TEV) protease. For these constructs, the Gly-6×His tag (SEQ ID NO: 421) was positioned on the N-terminus. Gly-6×His tags (SEQ ID NO: 421) are further described in Martos-Maldonado et al., Nat Commun. (2018) 17;9(1):3307, the disclosure of which is incorporated herein. Thus, in certain embodiments provided herein is a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 4 and a poly-His tag at the N-terminus, such as a Gly-6×His tag (SEQ ID NO: 421). In certain embodiments provided herein is a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 4, a poly-His tag at the N-terminus, such as a Gly-6×His tag (SEQ ID NO: 421), and/or a TEV cleavage site at the N-terminus. In certain embodiments provided herein is a nucleic acid-guided nuclease having a poly-His tag at the N-terminus, such as a Gly-6×His tag (SEQ ID NO: 421) and a TEV cleavage site at the N-terminus, such as a polypeptide having at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 2. In certain embodiments provided herein is a nucleic acid-guided nuclease disclosed herein includes a polypeptide having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 1, a poly-His tag at the N-terminus, such as a Gly-6×His tag (SEQ ID NO: 421), and/or a TEV cleavage site at the N-terminus. Additionally or alternatively, the nuclease may comprise one or more NLS as described herein.
Cleavage Sites In addition to, or alternatively to, including one or more NLSs, purification tags, and/or other additional amino acid sequences described herein, an engineered nuclease polypeptide disclosed herein can include one or more cleavage sites, which can be at or near the N-terminus or the C-terminus. Any suitable cleavage site can be used; if a plurality of cleavage sits is used, they may be the same or different. In certain embodiments a cleavage site comprises a Tobacco Etch Virus protease cleavage sequence, herein referred to as a “TEV sequence” (SEQ ID NO: 108). The TEV sequence can be at or near the amino terminus. Generally, the cleavage sequence, e.g., TEV sequence, is located so that cleavage at the cleavage sequence leaves other additional amino acid sequences, in particular any NLS added to the original nuclease polypeptide, intact. A TEV cleavage site can have the amino acid sequence ENLYFQS (SEQ ID. NO: 108.
In certain embodiments, provided herein is a nucleic acid sequence encoding a polypeptide having at least 50% nucleic acid identity to a polypeptide represented by SEQ ID NO: 2. In certain embodiments, provided herein is a nucleic acid sequence encoding a polypeptide having at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, greater than 95%, or 100% to a polypeptide represented by SEQ ID NO: 2. In certain embodiments, provided herein is a nucleic acid sequence encoding a polypeptide having at least at least 50% nucleic acid identity to a polypeptide represented by SEQ ID NO: 3. In certain embodiments, provided herein is a nucleic acid sequence encoding a polypeptide having at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, greater than 95%, or 100% to a polypeptide represented by SEQ ID NO: 3. In certain embodiments, provided herein is a nucleic acid sequence encoding a polypeptide having at least at least 50% nucleic acid identity to a polypeptide represented by SEQ ID NO: 4. In certain embodiments, provided herein is a nucleic acid sequence encoding a polypeptide having at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, greater than 95%, or 100% to a polypeptide represented by SEQ ID NO: 4. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 23-105. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 23-42 In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 43-65. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 43-53. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 54-58. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 59-63. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NO: 43. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 64-84. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NO: 64. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 64-74. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 75-79. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 80-84. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 85-105. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NO: 85. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 85-95. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 96-100. In certain embodiments, provided herein is a nucleic acid of at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% polynucleotide identity to any one of SEQ ID NOS: 101-105.
A nucleic acid sequence encoding a nucleic acid-guided nuclease can be operably linked to a promoter. Such nucleic acid sequences can be linear or circular. The nucleic acid sequences can be encompassed on a larger linear or circular nucleic acid sequences that comprises additional elements such as an origin of replication, selectable or screenable marker, terminator, other components of a targetable nuclease system, such as a guide nucleic acid, and/or an editing or recorder cassette as disclosed herein. In some aspects, nucleic acid sequences can include sequences that code for at least one glycine, at least one poly-histidine tag, such as a 6× histidine tag (SEQ ID NO: 423), and/or at least one, two, three, four, or five nuclear localization signal tags, some or all of which can be on the amino side of the polypeptide, the carboxy side of the polypeptide, or a combination thereof. Larger nucleic acid sequences can be recombinant expression vectors, as are described in more detail later.
Guide Nucleic Acids In certain embodiments, compositions and methods disclosed herein include a guide nucleic acid (gNA), e.g., a gRNA.
In general, a guide polynucleotide, also referred to as a guide nucleic acid (gNA) can complex with a compatible nucleic acid-guided nuclease, such as those disclosed herein, and can hybridize with a target nucleic acid sequence, thereby directing the nuclease to the target nucleic acid sequence. A subject nucleic acid-guided nuclease capable of complexing with a guide polynucleotide can be referred to as a nucleic acid-guided nuclease that is compatible with the guide polynucleotide. In addition, a guide polynucleotide capable of complexing with a nucleic acid-guided nuclease can be referred to as a guide polynucleotide or a guide nucleic acid that is compatible with the nucleic acid-guided nuclease. In some embodiments, a polynucleotide (gRNA) disclosed herein can be split into fragments, e.g., two separate polynucleotides, in some cases encompassing a synthetic tracrRNA and crRNA. Such gNAs, e.g., gRNAs, can be referred to as dual or split gNA, e.g., gRNA.
A guide polynucleotide can be DNA. A guide polynucleotide can be RNA. A guide polynucleotide can include both DNA and RNA. A guide polynucleotide can include modified or non-naturally occurring nucleotides. In cases where the guide polynucleotide comprises RNA, the RNA guide polynucleotide can be encoded by a DNA sequence on a polynucleotide molecule such as a plasmid, linear construct, or editing cassette as disclosed herein.
A guide polynucleotide can comprise a guide sequence, also referred to herein as a spacer sequence. A guide (spacer) sequence is a polynucleotide sequence having sufficient complementarity with a target polynucleotide sequence, also referred to herein as a target nucleic acid sequence, to hybridize with the target sequence and direct sequence-specific binding of a complexed nucleic acid-guided nuclease to the target sequence. The degree of complementarity between a guide sequence and its corresponding target sequence, when optimally aligned using a suitable alignment algorithm, is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97.5%, 99%, or more. Optimal alignment may be determined with the use of any suitable algorithm for aligning sequences. In some embodiments, a guide sequence can be about or more than about 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 75, or more nucleotides in length. In other embodiments, a guide sequence can be less than about 75, 50, 45, 40, 35, 30, 25, 20 nucleotides in length. Preferably the guide sequence is 10-30 nucleotides long. The guide sequence can be 15-20 nucleotides in length. The guide sequence can be 15 nucleotides in length. The guide sequence can be 16 nucleotides in length. The guide sequence can be 17 nucleotides in length. The guide sequence can be 18 nucleotides in length. The guide sequence can be 19 nucleotides in length. The guide sequence can be 20 nucleotides in length.
A guide polynucleotide can include a scaffold sequence. In general, a “scaffold sequence” can include any sequence that has sufficient sequence to promote formation of a targetable nuclease complex, wherein the targetable nuclease complex includes, but is not limited to, a nucleic acid-guided nuclease and a guide polynucleotide that can include a scaffold sequence and a guide sequence. Sufficient sequence within the scaffold sequence to promote formation of a targetable nuclease complex may include a degree of complementarity along the length of two sequence regions within the scaffold sequence, such as one or two sequence regions involved in forming a secondary structure. In some cases, the one or two sequence regions are included or encoded on the same polynucleotide. In some cases, the one or two sequence regions are included or encoded on separate polynucleotides. Optimal alignment may be determined by any suitable alignment algorithm, and may further account for secondary structures, such as self-complementarity within either the one or two sequence regions. In some embodiments, the degree of complementarity between the one or two sequence regions along the length of the shorter of the two when optimally aligned is about or more than about 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97.5%, 99%, or higher. In some embodiments, at least one of the two sequence regions can be about or more than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, or more nucleotides in length.
A scaffold sequence of a subject guide polynucleotide can comprise a secondary structure. A secondary structure can comprise a pseudoknot region. In some cases, binding kinetics of a guide polynucleotide to a nucleic acid-guided nuclease is determined in part by secondary structures within the scaffold sequence. In some cases, binding kinetics of a guide polynucleotide to a nucleic acid-guided nuclease is determined in part by nucleic acid sequence with the scaffold sequence. In some aspects, the invention provides a nuclease that binds to a guide polynucleotide can include a conserved scaffold sequence. For example, the nucleic acid-guided nucleases for use in the present disclosure can bind to a conserved pseudoknot region.
In certain embodiments, the engineered polynucleotide (gRNA) can be split into fragments encompassing a synthetic tracrRNA and crRNA.
As used herein, “guide nucleic acid” or “guide polynucleotide” can refer to one or more polynucleotides and can include 1) a guide (spacer) sequence capable of hybridizing to a target sequence and 2) a scaffold sequence capable of interacting with or complexing with a nucleic acid-guided nuclease as described herein. A guide nucleic acid can be provided as one or more nucleic acids. In specific embodiments, the guide sequence and the scaffold sequence are provided as a single polynucleotide. In other aspects, guide nucleic acid may include at least one amplicon targeting fragments.
A guide nucleic acid can be compatible with a nucleic acid-guided nuclease when the two elements can form a functional targetable nuclease complex capable of cleaving a target sequence. In certain methods, a compatible scaffold sequence for a compatible guide nucleic acid can be found by scanning sequences adjacent to a native nucleic acid-guided nuclease loci.
For example, native nucleic acid-guided nucleases can be encoded on a genome within proximity to a corresponding compatible guide nucleic acid or scaffold sequence.
Nucleic acid-guided nucleases can be compatible with guide nucleic acids that are not found within the nucleases endogenous host. Such orthogonal guide nucleic acids can be determined by empirical testing. Orthogonal guide nucleic acids can come from different bacterial species or be synthetic or otherwise engineered to be non-naturally occurring.
Orthogonal guide nucleic acids that are compatible with a common nucleic acid-guided nuclease can comprise one or more common features. Common features can include sequence outside a pseudoknot region. Common features can include a pseudoknot region. Common features can include a primary sequence or secondary structure.
A guide nucleic acid can be engineered to target a desired target sequence by altering the guide (spacer) sequence such that the guide sequence is complementary to the target sequence, thereby allowing hybridization between the guide sequence and the target sequence. A guide nucleic acid with an engineered guide sequence can be referred to as an engineered guide nucleic acid. Engineered guide nucleic acids are often non-naturally occurring and are not found in nature.
Engineered guide nucleic acids can be formed using a Synthetic Tracr RNA (STAR) system. STAR, when combined with a Cas12a protein, can form at least one ribonucleoprotein (RNP) complex that targets a specific genomic locus. STAR takes advantage of the natural properties of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) where the CRISPR system functions much like an immune system against invading viruses and plasmid DNA. Short DNA sequences (spacers) from invading viruses are incorporated at CRISPR loci within the bacterial genome and serve as “memory” of previous infections. Reinfection triggers complementary mature CRISPR RNA (crRNA) to find a matching viral sequence. Together, the crRNA and trans-activating crRNA (tracrRNA) guide CRISPR-associated (Cas) nuclease to cleave double-strand breaks in “foreign” DNA sequences. The prokaryotic CRISPR “immune system” has been engineered to function as an RNA-guided, mammalian genome editing tool that is simple, easy and quick to implement. STAR (which includes synthetic crRNA and tracrRNA) when combined with Cas12a protein can form ribonucleoprotein (RNP) complexes that target a specific genomic locus. Engineered guide nucleic acids formed with the RNA (STAR) system can result in a split gRNA. Split gRNA, i.e., dual guide RNAs are described more fully in WO 2021067788A1.
In certain embodiments, provided herein are ribonucleoprotein (RNP) complexes that include at least one nuclease disclosed herein. In certain embodiments, a RNP complex can include at least one nuclease having an amino acid sequence of at least 50% identity to SEQ ID NO:2. In certain embodiments, a RNP complex can include at least one nuclease having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO:2. In certain embodiments, a RNP complex can include at least one nuclease having an amino acid sequence of at least 50% identity to SEQ ID NO:3. In certain embodiments, a RNP complex can include at least one nuclease having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO:3. In certain embodiments, a RNP complex can include at least one nuclease having an amino acid sequence of at least 50% identity to SEQ ID NO:4. In certain embodiments, a RNP complex can include at least one nuclease having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO:4. In certain embodiments, a RNP complex including a nuclease disclosed herein can further include at least one STAR gRNA (dual guide RNA). In certain embodiments, a RNP complex including a nuclease disclosed herein can further include at least one non-STAR gRNA (e.g., single guide RNA). In certain embodiments, a RNP complex including a nuclease disclosed herein can further include at least one polynucleotide. In certain embodiments, a polynucleotide included in a RNP complex disclosed herein can be greater than about 50 nucleotides in length. In certain embodiments, a polynucleotide included in a RNP complex disclosed herein can be about 50, to about 150, to about 500, to about 1000 nucleotides, or greater than 1000 nucleotides in length. In certain embodiments, more than one nuclease can be added to an RNP complex to affect the overall editing efficiency. In certain embodiments, more than one gRNA can be added to the RNP complex to allow for multiplexed editing of more than one site in a single transfection for improved efficiency. In other embodiments, more than one DNA template can be added to the RNP to allow for multiplexed editing at one or more sites based on a specific desired repair outcome.
In certain embodiments, a composition comprising a Type V, e.g., Type VA, CRISPR nuclease polypeptide, such as described herein, further comprises a guide nucleic acid (gNA), e.g., gRNA, comprising a spacer sequence that targets a target nucleotide sequence (also referred to herein as a target nucleic acid sequence) within a polynucleotide (also referred to herein as a target polynucleotide, as will be clear from context), or a polynucleotide coding for the gNA, e.g., gRNA, wherein the gNA, e.g., gRNA is compatible with the Type V, e.g., Type VA, CRISPR nuclease. In general, a polynucleotide within which a target target nucleotide sequence (target nucleic acid sequence) is located, as that term is used herein, includes a polynucleotide that includes the target target nucleotide sequence (target nucleic acid sequence). Such a polynucleotide can be any suitable polynucleotide, such as a genome of a cell or part of a genome of a cell. In certain embodiments, the target nucleotide sequence (target nucleic acid sequence) is within 50 nucleotides of a protospacer adjacent motif (PAM) sequence specific for the Type V CRISPR nuclease, such as a PAM comprising a sequence of YTTN, wherein Y is T or C and N is A, T, G, or C, or a sequence of YTTV or TTTV, wherein V is A, G, or C. In certain embodiments the PAM comprises a sequence of YTTV or TTTV, wherein V is A, G, or C. In certain embodiments, the gNA is a gRNA, such as a dual (split) gRNA. The gNA, e.g. gRNA, can comprise one or more chemical modifications, such as 2′-O-alkyl, a 2′-O-methyl, a phosphorothioate, a phosphonoacetate, a thiophosphonoacetate, a 2′-O-methyl-3′-phosphorothioate, a 2′-O-methyl-3′-phosphonoacetate, a 2′-O-methyl-3′-thiophosphonoacetate, a 2′-deoxy-3′-phosphonoacetate, a 2′-deoxy-3′-thiophosphonoacetate, a suitable alternative, or a combination thereof. In certain embodiments, a ratio of guanine:uracil in the gRNA is at least 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:42, or 60:40, preferably at least 53:47, more preferably at least 54:46, even more preferably at least 55:45. See Example 12 and FIG. 10. In certain embodiments, a molar ratio of gNA, e.g., gRNA to Type V CRISPR nuclease is at least 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 2:1, 2.2:1, 2.5:1, or 3:1 and/or not more than 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 3:1, or 4:1, preferably 1.1:1 to 2.5:1, more preferably 1.2:1 to 2:1, even more preferably 1.2:1 to 1.7:1. See, e.g., Example 13. In certain embodiments a molar amount of gNA, e.g., gRNA, is at least 10, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 170, 190 or 200 pmol and/or not more than 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 170, 190, 200, 250, or 300 pmol, preferably 25-200 pmol, more preferably 50-100 pmol, even more preferably 65 to 85 pmol. See Example 13.
In certain embodiments, a composition comprising a Type V, e.g., Type VA, CRISPR nuclease polypeptide, such as described herein, further includes a donor template, also referred to as an editing template herein. A donor template can comprise homology arms, that is, nucleotide sequences that are complementary with polynucleotide sequences on either side of a cleavage site at which the donor template will be inserted. The donor template can be present in any suitable amount, e.g., in certain embodiments, at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.7, 2, 2.5, 3, 4, or 5 μg μL−1 and/or not more than 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.7, 2, 2.5, 3, 4, 5, 7, or 10 μg μL−1, preferably 0.3 to 2 μg μL−1, more preferably 0.5 to 1.5 μg μL−1, even more preferably 0.8 to 1.2 μg μL−1.
In certain embodiments, a composition comprising a Type V, e.g., Type VA, CRISPR nuclease polypeptide, such as described herein, further includes an anionic polymer. Any suitable anionic polymer may be used. Exemplary anionic polymers include 1,2,3-heptanetriol, 2-Amino-2-(hydroxymethyl)-1,3-propanediol (Tris), 3-(1-pyridino)-1-propane sulfonate (NDSB 201), 3[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 6-aminocaproic acid, adenosine diphosphate (ADP), adenosine triphosphate (ATP), alpha-cyclodextrin, amidosulfobetaine-14 (ASB-14), ammonium acetate, ammonium nitrate, ammonium sulfate, arginine, arginine ethylester, barium chloride, barium iodide, benzamidine HCl, beta-cyclodextrin, beta-mercaptoethanol (BME), biotin, calcium chloride, cesium chloride, cesium sulfate, cetyltrimethylammonium bromide (CTAB), choline chloride, citric acid, cobalt chloride, copper (II) chloride, cyclohexanol, D-sorbitol, dimethylethylammoniumpropane sulfonate (NDSB 195), dithiothreitol (DTT), erythritol, ethanol, ethylene glycol, ethylene glycol-bis(βbeta-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), ethylenediaminetetraacetic acid (EDTA), formamide, gadolinium bromide, gamma butyrolactone, glucose, glutamic acid, glutamine, glycerol, glycine, glycine betaine, glycine-glycine-glycine, guanidine HCl, guanosine triphosphate (GTP), holmium chloride, imidazole, iron (III) chloride, Jeffamine M-600, lanthanum acetate, lauryl sulfobetaine, lauryldimethylamine N-oxide (LDAO), lithium sulfate, magnesium chloride, magnesium sulfate, manganese chloride, mannitol, N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid) (EPPS), N-dodecyl beta-D-maltoside (DDM), N-ethylurea, n-hexanol, N-lauryl sarcoside, N-lauryl sarcosine, N-methylformamide, N-methylurea, n-octyl-b-D-glucoside (OG: Octyl glucoside), n-penthanol, nickel chloride, non-detergent sulfo betaine (NDSB), Nonidet P40 (NP40), octyl beta-D-glucopyranoside, poly-L-glutamic acid, polyethylene glycol (for example, PEG 300, PEG 3350, PEG 4000), polyethyleneglycol lauryl ether (Brij 35), polyoxyethylene (2) oleyl ether (Brij 93), polyoxyethylene cetyl ether (Brij 56), polyvinylpyrrolidone 40 (PVP40), potassium chloride, potassium citrate, potassium nitrate, proline, putrescine, spermidine, spermine, riboflavin, samarium bromide, sarcosine, sodium acetate, sodium chloride, sodium dodecyl sulfate (SDS), sodium fluoride, sodium iodide, sodium lauroyl sarcosinate (Sarkosyl), sodium malonate, sodium molybdate, sodium selenite, sodium sulfate, sodium thiocyanate, sucrose, taurine, trehalose, tricine, triethylamine, trimethylamine N-oxide (TMAO), tris(2-carboxyethyl)phosphine (TCEP), Triton X-100, Tween 20, Tween 60, Tween 80, urea, vitamin B12, xylitol, yttrium chloride, yttrium nitrate, zinc chloride, Zwittergent 3-08, Zwittergent 3-14, or a combination thereof. In certain embodiments, an anionic polymer comprises polyglutamic acid. In certain embodiments, the anionic polymer, e.g., PGA, is present at a concentration of at least 20, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 170, 200, 250, 300, 400, or 500 μg μL−1 and/or not more than 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 170, 200, 250, 300, 400, 500, 700, or 1000 μg μL−1, preferably 20 to 200 μg μL−1, more preferably 50 to 150 μg μL−1, even more preferably 80 to 120 μg μL−1 (PGA).
In certain embodiments, provided herein is a cell containing one or more of the compositions described herein, e.g. a composition comprising a Type V, e.g., Type VA, CRISPR nuclease polypeptide comprising one or more NLSs and, in certain embodiments a purification tag and/or cleavage site. Any suitable cell may be used. In certain embodiments the cell is a human cell, such as an immune cell, e.g., T cell, or a stem cell, e.g., induced pluripotent stem cell (iPSC).
In certain embodiments, provided herein are methods of inserting one or more of the compositions described herein, e.g., a composition comprising a Type V, e.g., Type VA, CRISPR nuclease polypeptide comprising one or more NLSs and, in certain embodiments a purification tag and/or cleavage site, into a cell. Any suitable method for insertion may be used. In certain embodiments, electroporation is used. Electroporation conditions can be optimized, see, e.g., Examples.
In certain embodiments provided are methods of modifying a target polynucleotide comprising contacting the target polynucleotide with a composition or compositions as described herein, e.g, a composition comprising a Type V, e.g., Type VA, CRISPR nuclease polypeptide comprising one or more NLSs and a suitable gNA, e.g., gRNA, and allowing the composition to modify the target polynucleotide, in some cases a genomic region, such as a genome or part of a genome within a cell, e.g. human cell such as an immune cell, e.g., T cell, or a stem cell, e.g., iPSC. In certain cases, the composition or compositions comprises a donor template, such as a donor template comprising a polynucleotide coding for a polypeptide to be expressed by the cell, in certain embodiments the polypeptide comprises a chimeric antigen receptor (CAR) or portion thereof; see, e.g., Examples. In certain embodiments the cell is a human cell, e.g., immune cell such as a T cell, or stem cell, such as an iPSC.
Nuclease Systems In certain embodiments disclosed herein are targetable nuclease systems. In certain embodiments, targetable nuclease system can include a nucleic acid-guided nuclease and a compatible guide nucleic acid (also referred to interchangeably herein as “guide polynucleotide” and “gRNA”). A targetable nuclease system can include a nucleic acid-guided nuclease or a polynucleotide sequence encoding the nucleic acid-guided nuclease. A targetable nuclease system can include a guide nucleic acid or a polynucleotide sequence encoding the guide nucleic acid.
In general, a targetable nuclease system as disclosed herein can be characterized by elements that promote the formation of a targetable nuclease complex at the site of a target sequence, wherein the targetable nuclease complex includes a nucleic acid-guided nuclease and a guide nucleic acid.
A guide nucleic acid together with a nucleic acid-guided nuclease forms a targetable nuclease complex which is capable of binding to a target sequence within a target polynucleotide, as determined by the guide sequence of the guide nucleic acid.
In general, to generate a double stranded break, in most cases a targetable nuclease complex binds to a target sequence as determined by the guide nucleic acid, and the nuclease has to recognize a protospacer adjacent motif (PAM) sequence adjacent to the target sequence.
A targetable nuclease complex can include a nucleic acid-guided nuclease having an amino acid sequence of at least 50% identity to SEQ ID NO: 2 and a compatible guide nucleic acid. A targetable nuclease complex can include a nucleic acid-guided nuclease having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences SEQ ID NO: 2 and a compatible guide nucleic acid. protospacer adjacent motif (PAM) sequence adjacent to the target sequence. A targetable nuclease complex can include a nucleic acid-guided nuclease having an amino acid sequence of at least 50% identity to SEQ ID NO: 3 and a compatible guide nucleic acid. A targetable nuclease complex can include a nucleic acid-guided nuclease having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 3 and a compatible guide nucleic acid. A targetable nuclease complex can include a nucleic acid-guided nuclease having an amino acid sequence of at least 50% identity to SEQ ID NO: 4 and a compatible guide nucleic acid. A targetable nuclease complex can include a nucleic acid-guided nuclease having an amino acid sequence of at least about 60%, 65%, 75%, 85%, 95%, 99% or about 100% identity to amino acid sequences of SEQ ID NO: 4 and a compatible guide nucleic acid. In certain embodiments, the guide nucleic acid can include a scaffold sequence compatible with the nucleic acid-guided nuclease selected. In any of these embodiments, the guide sequence can be engineered to be complementary to any desired target sequence. The guide sequence selected can be engineered to hybridize to any desired target sequence. In certain embodiments, the guide sequence is a dual guide RNA.
A target sequence of a targetable nuclease complex can be any polynucleotide endogenous or exogenous to a prokaryotic or eukaryotic cell, or in vitro. For example, the target sequence can be a polynucleotide residing in the nucleus of the eukaryotic cell. A target sequence can be a sequence coding a gene product (e.g., a protein) or a non-coding sequence (e.g., a regulatory polynucleotide or a junk DNA). It is contemplated herein that the target sequence should be associated with a PAM; that is, a short sequence recognized by a targetable nuclease complex. The precise sequence and length requirements for a PAM differ depending on the nucleic acid-guided nuclease used, but PAMs can be a 2-5 base pair sequences adjacent the target sequence. Examples of PAM sequences are given in the examples section below, and the skilled person will be able to identify further PAM sequences for use with a given nucleic acid-guided nuclease. Further, engineering of the PAM Interacting (PI) domain may allow programming of PAM specificity, improve target site recognition fidelity, and increase the versatility of a nucleic acid-guided nuclease genome engineering platform. Nucleic acid-guided nucleases may be engineered to alter their PAM specificity, for example as described in Kleinstiver et al., Nature. 2015 Jul. 23; 523 (7561): 481-5, the disclosure of which is incorporated herein in its entirety.
A PAM site is a nucleotide sequence in proximity to a target sequence. In most cases, a nucleic acid-guided nuclease can only cleave a target sequence if an appropriate PAM is present. PAMs are nucleic acid-guided nuclease-specific and can be different between two different nucleic acid-guided nucleases. A PAM can be 5′ or 3′ of a target sequence. A PAM can be upstream or downstream of a target sequence. A PAM can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more nucleotides in length. Often, a PAM is between 2-6 nucleotides in length.
In some embodiments disclosed herein, a PAM can be provided on a separate oligonucleotide. In such cases, providing PAM on a oligonucleotide allows cleavage of a target sequence that otherwise would not be able to be cleave because no adjacent PAM is present on the same polynucleotide as the target sequence.
Polynucleotide sequences encoding a component of a targetable nuclease system can include one or more vectors. In general, the term “vector” as used herein can refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. Vectors include, but are not limited to, nucleic acid molecules that are single-stranded, double-stranded, or partially double-stranded; nucleic acid molecules that comprise one or more free ends, no free ends (e.g. circular); nucleic acid molecules that comprise DNA, RNA, or both; and other varieties of polynucleotides known in the art. One type of vector is a “plasmid,” which refers to a circular double stranded DNA loop into which additional DNA segments can be inserted, such as by standard molecular cloning techniques. Another type of vector is a viral vector, wherein virally-derived DNA or RNA sequences are present in the vector for packaging into a virus (e.g. retroviruses, replication defective retroviruses, adenoviruses, replication defective adenoviruses, and adeno-associated viruses). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell. Recombinant expression vectors can include a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, can mean that the recombinant expression vectors include one or more regulatory elements, which may be selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed.
In some embodiments, a regulatory element can be operably linked to one or more elements of a targetable nuclease system so as to drive expression of the one or more components of the targetable nuclease system.
In some embodiments, a vector can include a regulatory element operably linked to a polynucleotide sequence encoding a nucleic acid-guided nuclease. The polynucleotide sequence encoding the nucleic acid-guided nuclease can be codon optimized for expression in targeted cells, such as prokaryotic or eukaryotic cells. Eukaryotic cells can be yeast, fungi, algae, plant, animal, or human cells. Eukaryotic cells can be those derived from an organism, such as a mammal, including but not limited to human, mouse, rat, rabbit, dog, or non-human mammal including non-human primate.
In general, codon optimization can refer to a process of modifying a nucleic acid sequence for enhanced expression in the host cells of interest by replacing at least one codon or more of the native sequence with codons that are more frequently or most frequently used in the genes of that host cell while maintaining the native amino acid sequence. Various species exhibit certain bias for codons of a certain amino acid. As contemplated herein, genes can be tailored for optimal gene expression in a given organism based on codon optimization. Codon usage tables are readily available, for example, at the “Codon Usage Database” available at www.kazusa.orjp and these tables can be adapted in a number of ways. See Nakamura, Y., et al. “Codon usage tabulated from the international DNA sequence databases: status for the year 2000” Nucl. Acids Res. 28:292 (2000).
A nucleic acid-guided nuclease and one or more guide nucleic acids can be delivered either as DNA or RNA. Delivery of a nucleic acid-guided nuclease and guide nucleic acid both as RNA (unmodified or containing base or backbone modifications) molecules can be used to reduce the amount of time that the nucleic acid-guided nuclease persists in the cell. This may reduce the level of off-target cleavage activity in the target cell. Since a nucleic acid-guided nuclease as mRNA takes time to be translated into protein, it can be advantageous to deliver the guide nucleic acid several hours following the delivery of the nucleic acid-guided nuclease mRNA, to maximize the level of guide nucleic acid available for interaction with the nucleic acid-guided nuclease protein. In other cases, the nucleic acid-guided nuclease mRNA and guide nucleic acid are delivered concomitantly. In other examples, the guide nucleic acid is delivered sequentially, such as 0.5, 1, 2, 3, 4, or more hours after the nucleic acid-guided nuclease mRNA.
Guide nucleic acid in the form of RNA or encoded on a DNA expression cassette can be introduced into a host cell can include a nucleic acid-guided nuclease encoded on a vector or chromosome. The guide nucleic acid may be provided in the cassette one or more polynucleotides, which may be contiguous or non-contiguous in the cassette. In specific embodiments, the guide nucleic acid is provided in the cassette as a single contiguous polynucleotide.
A variety of delivery systems can be used to introduce a nucleic acid-guided nuclease (DNA or RNA) and guide nucleic acid (DNA or RNA) into a host cell. In accordance with these embodiments, systems of use can include, but are not limited to, yeast systems, lipofection systems, microinjection systems, biolistic systems, virosomes, liposomes, immunoliposomes, polycations, lipid:nucleic acid conjugates, virions, artificial virions, viral vectors, electroporation, cell permeable peptides, nanoparticles, nanowires (Shalek et al., Nano Letters, 2012), exosomes. Molecular trojan horses liposomes (Pardridge et al., Cold Spring Harb Protoc; 2010; doi:10.1101/pdb.prot5407) may be used to deliver an engineered nuclease and guide nuclease across the blood brain barrier.
In some embodiments, an editing template, also referred to herein as a donor template, is also provided. An editing template may be a component of a vector as described herein, contained in a separate vector, or provided as a separate polynucleotide, such as an oligonucleotide, linear polynucleotide, or synthetic polynucleotide. In some cases, an editing template is on the same polynucleotide as a guide nucleic acid. In some embodiments, an editing template is designed to serve as a template in homologous recombination, such as within or near a target sequence nicked or cleaved by a nucleic acid-guided nuclease as a part of a complex as disclosed herein. An editing template polynucleotide can be of any suitable length, such as about or more than about 10, 15, 20, 25, 50, 75, 100, 150, 200, 500, 1000, or more nucleotides in length. In some embodiments, the editing template polynucleotide is complementary to a portion of a polynucleotide can include the target sequence. When optimally aligned, an editing template polynucleotide might overlap with one or more nucleotides of a target sequences (e.g. about or more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, or more nucleotides). In some embodiments, when a editing template sequence and a polynucleotide can include a target sequence are optimally aligned, the nearest nucleotide of the template polynucleotide is within about 1, 5, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 1000, 5000, 10000, or more nucleotides from the target sequence.
In some embodiments, methods are provided for delivering one or more polynucleotides, such as or one or more vectors or linear polynucleotides as described herein, one or more transcripts thereof, and/or one or proteins transcribed therefrom, to a host cell. In some aspects, the invention further provides cells produced by such methods, and organisms can include or produced from such cells. In some embodiments, an engineered nuclease in combination with (and optionally complexed with) a guide nucleic acid is delivered to a cell.
Conventional viral and non-viral based gene transfer methods can be used to introduce nucleic acids in cells, such as prokaryotic cells, eukaryotic cells, mammalian cells, or target tissues. Such methods can be used to administer nucleic acids encoding components of an engineered nucleic acid-guided nuclease system to cells in culture, or in a host organism. Non-viral vector delivery systems include DNA plasmids, RNA (e.g. a transcript of a vector described herein), naked nucleic acid, and nucleic acid complexed with a delivery vehicle, such as a liposome. Viral vector delivery systems include DNA and RNA viruses, which have either episomal or integrated genomes after delivery to the cell. Any gene therapy method known in the art is contemplated of use herein. Methods of non-viral delivery of nucleic acids include are contemplated herein. Adeno-associated virus (“AAV”) vectors may also be used to transduce cells with target nucleic acids, e.g., in the in vitro production of nucleic acids and peptides, and for in vivo and ex vivo gene therapy procedures.
In some embodiments, a host cell is transiently or non-transiently transfected with one or more vectors, linear polynucleotides, polypeptides, nucleic acid-protein complexes, or any combination thereof as described herein. In some embodiments, a cell in transfected in vitro, in culture, or ex vivo. In some embodiments, a cell is transfected as it naturally occurs in a subject. In some embodiments, a cell that is transfected is taken from a subject. In some embodiments, the cell is derived from cells taken from a subject, such as a cell line.
In some embodiments, a cell transfected with one or more vectors, linear polynucleotides, polypeptides, nucleic acid-protein complexes, or any combination thereof as described herein is used to establish a new cell line can include one or more transfection-derived sequences. In some embodiments, a cell transiently transfected with the components of an engineered nucleic acid-guided nuclease system as described herein (such as by transient transfection of one or more vectors, or transfection with RNA), and modified through the activity of an engineered nuclease complex, is used to establish a new cell line can include cells containing the modification but lacking any other exogenous sequence.
In some embodiments, one or more vectors described herein are used to produce a non-human transgenic cell, organism, animal, or plant. In some embodiments, the transgenic animal is a mammal, such as a mouse, rat, or rabbit. Methods for producing transgenic cells, organisms, plants, and animals are known in the art, and generally begin with a method of cell transformation or transfection, such as described herein.
In certain embodiments, an engineered nuclease complex, “target sequence” can refer to a sequence to which a guide sequence is designed to have complementarity, where hybridization between a target sequence and a guide sequence promotes the formation of an engineered nuclease complex. A target sequence can include any polynucleotide, such as DNA, RNA, or a DNA-RNA hybrid. A target sequence can be located in the nucleus or cytoplasm of a cell. A target sequence can be located in vitro or in a cell-free environment.
In some embodiments, formation of an engineered nuclease complex can include a guide nucleic acid hybridized to a target sequence and complexed with one or more novel engineered nucleases as disclosed herein renders cleavage of one or both strands in or near (e.g. within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, or more base pairs from) the targeted sequence. Cleavage can occur within a target sequence, 5′ of the target sequence, upstream of a target sequence, 3′ of the target sequence, or downstream of a target sequence.
In some embodiments, one or more vectors driving expression of one or more components of a targetable nuclease system are introduced into a host cell or in vitro such formation of a targetable nuclease complex at one or more target sites. For example, a nucleic acid-guided nuclease and a guide nucleic acid can each be operably linked to separate regulatory elements on separate vectors. Alternatively, two or more of the elements expressed from the same or different regulatory elements, can be combined in a single vector, with one or more additional vectors providing any components of the targetable nuclease system not included in the first vector. Targetable nuclease system elements that are combined in a single vector may be arranged in any suitable orientation, such as one element located 5′ with respect to (“upstream” of) or 3′ with respect to (“downstream” of) a second element. The coding sequence of one element may be located on the same or opposite strand of the coding sequence of a second element, and oriented in the same or opposite direction. In some embodiments, a single promoter drives expression of a transcript encoding a nucleic acid-guided nuclease and one or more guide nucleic acids. In some embodiments, a nucleic acid-guided nuclease and one or more guide nucleic acids are operably linked to and expressed from the same promoter. In other embodiments, one or more guide nucleic acids or polynucleotides encoding the one or more guide nucleic acids are introduced into a cell or in vitro environment already can include a nucleic acid-guided nuclease or polynucleotide sequence encoding the nucleic acid-guided nuclease.
In some embodiments, when multiple different guide sequences are used, a single expression construct may be used to target nuclease activity to multiple different, corresponding target sequences within a cell or in vitro. For example, a single vector can include about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more guide sequences. In other embodiments, about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more such guide-sequence-containing vectors can be provided, and optionally, delivered to a cell in vivo or in vitro.
In some embodiments, methods and compositions disclosed herein can include more than one guide nucleic acid, such that each guide nucleic acid has a different guide sequence, thereby targeting a different target sequence. In accordance with these embodiments, multiple guide nucleic acids can be using in multiplexing, wherein multiple targets are targeted simultaneously. Additionally or alternatively, the multiple guide nucleic acids are introduced into a population of cells, such that each cell in a population received a different or random guide nucleic acid, thereby targeting multiple different target sequences across a population of cells. In such cases, the collection of subsequently altered cells can be referred to as a library.
In other embodiments, methods and compositions disclosed herein can include multiple different nucleic acid-guided nucleases, each with one or more different corresponding guide nucleic acids, thereby allowing targeting of different target sequences by different nucleic acid-guided nucleases. In some such cases, each nucleic acid-guided nuclease can correspond to a distinct plurality of guide nucleic acids, allowing two or more non-overlapping, partially overlapping, or completely overlapping multiplexing events.
In some embodiments, the nucleic acid-guided nuclease has DNA cleavage activity or RNA cleavage activity. In some embodiments, the nucleic acid-guided nuclease directs cleavage of one or both strands at the location of a target sequence, such as within the target sequence and/or within the complement of the target sequence. In some embodiments, the nucleic acid-guided nuclease directs cleavage of one or both strands within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 200, 500, or more base pairs from the first or last nucleotide of a target sequence.
In certain embodiments, the invention provides for methods of modifying a target sequence in vitro, or in a prokaryotic or eukaryotic cell, which can be in vivo, ex vivo, or in vitro. In some embodiments, the method includes sampling a cell or population of cells such as prokaryotic cells, or those from a human or non-human animal or plant (including micro-algae or other organism), and modifying the cell or cells. Culturing may occur at any stage in vitro or ex vivo. The cell or cells may even be re-introduced into the host, such as a non-human animal or plant (including micro-algae). For re-introduced cells, they can be stem cells.
In some embodiments, the method includes allowing a targetable nuclease complex to bind to the target sequence to effect cleavage of the target sequence, thereby modifying the target sequence, wherein the targetable nuclease complex includes a nucleic acid-guided nuclease complexed with a guide nucleic acid wherein the guide sequence of the guide nucleic acid is hybridized to a target sequence within a target polynucleotide. In some aspects, the invention provides a method of modifying expression of a target polynucleotide in in vitro or in a prokaryotic or eukaryotic cell. In some embodiments, the method includes allowing an targetable nuclease complex to bind to a target sequence with the target polynucleotide such that the binding can lead to in increased or decreased expression of the target polynucleotide; wherein the targetable nuclease complex includes an nucleic acid-guided nuclease complexed with a guide nucleic acid, and wherein the guide sequence of the guide nucleic acid is hybridized to a target sequence within the target polynucleotide.
In certain embodiments, the invention provides kits containing any one or more of the elements disclosed in the above methods and compositions. Elements may provide individually or in combinations, and may be provided in any suitable container, such as a vial, a bottle, or a tube. In some embodiments, the kit includes instructions in one or more languages, for example in more than one language.
In some embodiments, a kit comprises one or more reagents for use in a process utilizing one or more of the elements described herein. Reagents may be provided in any suitable container. For example, a kit may provide one or more reaction or storage buffers. Reagents can be provided in a form that is usable in an assay, or in a form that requires addition of one or more other components before use (e.g. in concentrate or lyophilized form). A buffer can be any buffer, including but not limited to a sodium carbonate buffer, a sodium bicarbonate buffer, a borate buffer, a Tris buffer, a MOPS buffer, a HEPES buffer, and combinations thereof. In some embodiments, the buffer is alkaline. In some embodiments, the buffer has a pH from about 7 to about 10. In some embodiments, the kit includes one or more oligonucleotides corresponding to a guide sequence for insertion into a vector so as to operably link the guide sequence and a regulatory element. In some embodiments, the kit includes a editing template.
In some embodiments, a targetable nuclease complex has a wide variety of utility including modifying (e.g., deleting, inserting, translocating, inactivating, activating) a target sequence in a multiplicity of cell types. As such a targetable nuclease complex of the invention has a broad spectrum of applications in, e.g., biochemical pathway optimization, genome-wide studies, genome engineering, gene therapy, drug screening, disease diagnosis, and prognosis. An exemplary targetable nuclease complex includes a nucleic acid-guided nuclease as disclosed herein complexed with a guide nucleic acid, wherein the guide sequence of the guide nucleic acid can hybridize to a target sequence within the target polynucleotide. A guide nucleic acid can include a guide sequence linked to a scaffold sequence. A scaffold sequence can include one or more sequence regions with a degree of complementarity such that together they form a secondary structure.
An editing template polynucleotide can include a sequence to be integrated (e.g., a mutated gene). A sequence for integration may be a sequence endogenous or exogenous to the cell. Examples of a sequence to be integrated include polynucleotides encoding a protein or a non-coding RNA (e.g., a microRNA). Thus, the sequence for integration may be operably linked to an appropriate control sequence or sequences. Alternatively, the sequence to be integrated may provide a regulatory function. Sequence to be integrated may be a mutated or variant of an endogenous wild-type sequence. Alternatively, sequence to be integrated may be a wild-type version of an endogenous mutated sequence. Additionally or alternatively, sequenced to be integrated may be a variant or mutated form of an endogenous mutated or variant sequence.
In certain embodiments, an upstream or downstream sequence can include from about 20 bp to about 2500 bp, for example, about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, or about 2500 bp. In some embodiments, an exemplary upstream or downstream sequence has about 15 bp to about 2000 bp, about 30 bp to about 1000 bp, about 50 bp to about 750 bp, about 600 bp to about 1000 bp, or about 700 bp to about 1000 bp.
In some embodiments, the editing template polynucleotide can further include a marker. In certain embodiments, some markers can facilitate screening for targeted integrations. Examples of suitable markers can include, but are not limited to, restriction sites, fluorescent proteins, or selectable markers. In certain embodiments, an exogenous polynucleotide template can be constructed using recombinant techniques.
In one embodiment, an exemplary method for modifying a target polynucleotide by integrating an editing template polynucleotide, a double stranded break is introduced into the genome sequence by an engineered nuclease complex, the break can be repaired via homologous recombination using an editing template such that the template is integrated into the target polynucleotide. The presence of a double-stranded break can increase the efficiency of integration of the editing template.
Disclosed herein are methods for modifying expression of a polynucleotide in a cell. Some methods include increasing or decreasing expression of a target polynucleotide by using a targetable nuclease complex that binds to the target polynucleotide.
Detection of the gene expression level can be conducted in real time in an amplification assay. In one aspect, the amplified products can be directly visualized with fluorescent DNA-binding agents including but not limited to DNA intercalators and DNA groove binders. Because the amount of the intercalators incorporated into the double-stranded DNA molecules can be proportional to the amount of the amplified DNA products, one can conveniently determine the amount of the amplified products by quantifying the fluorescence of the intercalated dye using conventional optical systems in the art. DNA-binding dye suitable for this application include, but are not limited to, SYBR green, SYBR blue, DAPI, propidium iodine, Hoeste, SYBR gold, ethidium bromide, acridines, proflavine, acridine orange, acriflavine, fluorcoumanin, ellipticine, daunomycin, chloroquine, distamycin D, chromomycin, homidium, mithramycin, ruthenium polypyridyls, anthramycin, and others known by one of skill in the art.
In some embodiments, other fluorescent labels such as sequence specific probes can be employed in the amplification reaction to facilitate the detection and quantification of the amplified products. Probe-based quantitative amplification relies on the sequence-specific detection of a desired amplified product. It utilizes fluorescent, target-specific probes (e.g., TaqMan™ probes) resulting in increased specificity and sensitivity. Methods for performing probe-based quantitative amplification are well established in the art.
In some embodiments, an agent-induced change in expression of sequences associated with a signaling biochemical pathway can also be determined by examining the corresponding gene products. Determining the protein level can involve a) contacting the protein contained in a biological sample with an agent that specifically bind to a protein associated with a signaling biochemical pathway; and (b) identifying any agent:protein complex so formed. In one aspect of this embodiment, the agent that specifically binds a protein associated with a signaling biochemical pathway is an antibody, preferably a monoclonal antibody.
In some embodiments, the amount of agent:polypeptide complexes formed during the binding reaction can be quantified by standard quantitative assays. As illustrated above, the formation of agent:polypeptide complex can be measured directly by the amount of label remained at the site of binding. In an alternative, the protein associated with a signaling biochemical pathway is tested for its ability to compete with a labeled analog for binding sites on the specific agent. In this competitive assay, the amount of label captured is inversely proportional to the amount of protein sequences associated with a signaling biochemical pathway present in a test sample.
In some embodiments, a number of techniques for protein analysis based on the general principles outlined above are known in the art and contemplated herein. They include but are not limited to radioimmunoassays, ELISA (enzyme linked immunoradiometric assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays (using e.g., colloidal gold, enzyme or radioisotope labels), western blot analysis, immunoprecipitation assays, immunofluorescent assays, and SDS-PAGE.
In some embodiments, in practicing a subject method, it may be desirable to discern the expression pattern of a protein associated with a signaling biochemical pathway in different bodily tissue, in different cell types, and/or in different subcellular structures. These studies can be performed with the use of tissue-specific, cell-specific or subcellular structure specific antibodies capable of binding to protein markers that are preferentially expressed in certain tissues, cell types, or subcellular structures.
In other embodiment, an altered expression of a gene associated with a signaling biochemical pathway can also be determined by examining a change in activity of the gene product relative to a control cell. The assay for an agent-induced change in the activity of a protein associated with a signaling biochemical pathway will dependent on the biological activity and/or the signal transduction pathway that is under investigation. For example, where the protein is a kinase, a change in its ability to phosphorylate the downstream substrate(s) can be determined by a variety of assays known in the art. Representative assays include but are not limited to immunoblotting and immunoprecipitation with antibodies such as anti-phosphotyrosine antibodies that recognize phosphorylated proteins. In addition, kinase activity can be detected by high throughput chemiluminescent assays.
In certain embodiments, where the protein associated with a signaling biochemical pathway is part of a signaling cascade leading to a fluctuation of intracellular pH condition, pH sensitive molecules such as fluorescent pH dyes can be used as the reporter molecules. In another example where the protein associated with a signaling biochemical pathway is an ion channel, fluctuations in membrane potential and/or intracellular ion concentration can be monitored. A number of commercial kits and high-throughput devices are suited for a rapid and robust screening for modulators of ion channels. Representative instruments include FLIPR™ (Molecular Devices, Inc.) and VIPR (Aurora Biosciences). These instruments are capable of detecting reactions in over 1000 sample wells of a microplate simultaneously, and providing real-time measurement and functional data within a second or even a millisecond.
In practicing any of the methods disclosed herein, a suitable vector can be introduced to a cell, tissue, organism, or an embryo via one or more methods known in the art, including without limitation, microinjection, electroporation, sonoporation, biolistics, calcium phosphate-mediated transfection, cationic transfection, liposome transfection, dendrimer transfection, heat shock transfection, nucleofection transfection, magnetofection, lipofection, impalefection, optical transfection, proprietary agent-enhanced uptake of nucleic acids, and delivery via liposomes, immunoliposomes, virosomes, or artificial virions. In some methods, the vector is introduced into an embryo by microinjection. The vector or vectors may be microinjected into the nucleus or the cytoplasm of the embryo. In some methods, the vector or vectors may be introduced into a cell by nucleofection.
A target polynucleotide of a targetable nuclease complex can be any polynucleotide endogenous or exogenous to the host cell. For example, the target polynucleotide can be a polynucleotide residing in the nucleus of the eukaryotic cell, the genome of a prokaryotic cell, or an extrachromosomal vector of a host cell. The target polynucleotide can be a sequence coding a gene product (e.g., a protein) or a non-coding sequence (e.g., a regulatory polynucleotide or a junk DNA).
Some embodiments disclosed herein relate to use of an engineered nucleic acid guided nuclease system disclosed herein; for example, in order to target and knock out genes, amplify genes and/or repair certain mutations associated with DNA repeat instability and a medical disorder. This nuclease system may be used to harness and to correct these defects of genomic instability. In other embodiments, engineered nucleic acid guided nuclease systems disclosed herein can be used for correcting defects in the genes associated with Lafora disease. Lafora disease is an autosomal recessive condition which is characterized by progressive myoclonus epilepsy which may start as epileptic seizures in adolescence. This condition causes seizures, muscle spasms, difficulty walking, dementia, and eventually death.
In yet another aspect of the invention, the engineered/novel nucleic acid guided nuclease system can be used to correct genetic-eye disorders that arise from several genetic mutations
In certain embodiments disclosed herein engineered nucleic acid guided nuclease constructs can recognize a protospacer adjacent motif (PAM) sequence other than TTTN or in addition to TTTN. In other embodiments, engineered nucleic acid guided nuclease constructs disclosed herein can be further mutated to improve targeting efficiency or can be selected from a library for certain targeted features. Other embodiments disclosed herein concern vectors including constructs disclosed herein of use for further analysis and to select for improved genome editing features.
Other embodiments disclosed herein include kits for packaging and transporting nucleic acid guided nuclease constructs and/or novel gRNAs disclosed herein or known gRNAs disclosed herein and further include at least one container. In certain embodiments, several reagents required for the kits can be included for convenience and ease of transport and efficiency.
EXAMPLES Example 1: Culture of Jurkat Human T-Cell Leukemia Cell Line and Primary Human T-Cells Human Jurkat T-cell leukemia cells (Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH (ACC 282)) were propagated in RPMI 1640 medium (ThermoFisher Scientific) with 10% heat-inactivated fetal bovine serum (FBS) (ThermoFisher Scientific) supplemented with 1% penicillin-streptomycin antibiotic mix (ThermoFisher Scientific). Cells were cultured at 37° C. in 5% CO2 incubators and maintained at a density of 0.5 to 1.5×106 cells mL−1. 24 hours before transfection, cells were passaged at 0.1×106 cell mL−1. Cell culture media supernatant was periodically tested for mycoplasma contamination using the MycoAlert PLUS mycoplasma detection kit (Lonza).
Example 2: Primary T-Cell Isolation and Culture T-cells were isolated from human peripheral blood obtained from healthy adults by immune-magnetic negative selection using the EasySep Human T-cell Isolation Kit (STEMCELL Technologies). After isolation, T-cells were activated in 25 μL mL−1 ImmunoCult Human CD3/CD28/CD2 T-Cell Activator (STEMCELL Technologies) in ImmunoCult-XF T-Cell Expansion Medium (STEMCELL Technologies) containing 12.5 ng mL−1 Human Recombinant IL-2, 5 ng mL−1 IL-7, and 5 ng mL−1 IL-15 (STEMCELL Technologies) and seeded at 1.0×106 cells mL−1. Until transfection 48 hours later, the cells were cultured at 37° C. in 5% CO2 incubators.
Example 3: RNP Formulation Ribonucleoprotein complexes (RNPs) were generated by incubating respective guide nucleic acids (gNAs) with MAD7 in the molar ratio of 3:2 gNA:MAD7 for 15 minutes at room temperature immediately before transfection. For Jurkat experiments, the RNP complexes were generated by mixing the respective gNA (150 pmol), MAD7 (100 pmol), and nuclease-free water, unless otherwise stated. For T-cell experiments, 1.6 μL of an aqueous solution of 15-50 kDa poly-L-glutamic acid (PGA, 100 μg Alamanda Polymers) was added to gNAs, followed by the addition of MAD7 and nuclease-free water.
Example 4: Generation of Donor Templates Via PCT Amplification Donor templates comprising site-specific homology arms, respective promoter, and respective gene (GFP or Hu19 scFv-CD8α-CD28-CD3ζ CAR) were amplified from corresponding pTwist Ampicillin high-copy plasmids (Twist Bioscience) using homology arms-specific PCR primers. Donor templates were amplified in a two-step PCR program: initial denaturation at 98° C. for 30 seconds, cycle denaturation at 98° C. for 10 seconds, extension at 72° C. for 30 seconds per kb amplicon for 40-cycles with a hold at 72° C. for 10 minutes. Each 50 PCR reaction contained 10 ng amplification template (plasmid DNA), 0.5 μM homology arm-specific forward and reverse primers, nuclease-free water (IDT), 3% DMSO, and 1× Phusion High-Fidelity PCR Master Mix with HF Buffer (ThermoFisher Scientific). PCR products were purified using NucleoSpin Gel and PCR Clean-up Kit (Macherey-Nagel) with two 20 μL elutions. Purified HDR templates were collected and quantified on NanoDrop One Microvolume UV-Vis Spectrophotometer (ThermoFisher Scientific). Templates were concentrated using Amicon Ultra 0.5 mL 30K Centrifugal Filters: 100 μg DNA per unit was transferred, filled with nuclease-free water to 500 μL, and centrifuged at 10,000 g for 10 minutes to reduce volume to 50 μL. DNA was washed twice with nuclease-free water and recovered into a fresh tube by inversion and centrifugation at 10,000 g for 15 seconds. HDR templates were collected, diluted, and concentrations quantified using Qubit dsDNA HS Assay Kit (ThermoFisher Scientific). HDR templates of 0.5 to 1 μg μL−1 were used for cellular studies.
Example 5: Jurkat Cell Transfection Lonza 4D Nucleofector with Shuttle unit (V4SC-2960 Nucleocuvette Strips) was used for transfection, following the manufacturer's instructions. For transfection, cells were harvested by centrifugation (200 g, RT, 5 minutes) and re-suspended in 20 μL at 10×106 cells mL−1 in the SF Cell Line Nucleofector X Kit buffer (Lonza), unless stated otherwise. The cell suspension was mixed with the RNPs, immediately transferred to the nucleocuvette, and transfected. After transfection, the cells were immediately re-suspended in the pre-warmed cultivation medium and plated onto 96-well, flat-bottom, non-cell culture treated plates (Falcon), and cultured at 37° C. in 5% CO2 incubators and maintained at a density of 0.5 to 1.0×106 cells mL−1. After 48 hours, the cells were harvested for the viability assay and genomic DNA, as described below. For the Homology-Directed Repair Template insertion, the HDR template was added to the cells and the suspension transferred to the RNPs immediately before transfection. The transfection parameters, cell recovery step, and proliferation conditions as described in Example 1. The cells were harvested 48 hours post-transfection for the viability assessment, after 7 days for CAR insertion efficiency, or after 7 days, 14 days, and 21 days for GFP insertion efficiency.
Example 6: Primary T-Cell Transfection 48 hours after isolation, the cells were harvested by centrifugation (300 g, RT, 5 minutes) and re-suspended in 20 μL at 50×106 cells mL−1 in the supplemented P3 Primary Cell Nucleofector Kit buffer (Lonza). The cells were mixed with HDR templates and the suspension transferred to the RNPs immediately before transfection (Nucleofection program EH-115). After transfection, 80 μL of pre-warmed cultivation medium without IL-2 was added to the electroporation cuvettes. When using M3814 (Selleckchem), 80 μL of pre-warmed cultivation medium containing 2 μM M3814 final concentration without IL-2 was added to the electroporation cuvettes. After 10 minutes of incubation at 37° C., T-cells were transferred onto 96-well, flat-bottom, non-cell culture treated plates (Falcon) containing pre-warmed cultivation medium pretreated with 2 μM M3814 final concentration and 12.5 ng mL−1 IL-2. The cells were seeded at a density of 0.25×106 cells mL−1, or 1.3×106 cells mL−1 in the experiment with M3814, and kept at 37° C. in 5% CO2 incubators. The viability assay was carried out 24 hours post-transfection after which the cells were reseeded in the fresh cultivation medium containing IL-2. Insertion efficiency of CAR was measured after 7 days, and 11 days or 13 days post-transfection.
Example 7: Flow Cytometry Flow cytometric assessments were carried out on a CytoFLEX S instrument (Beckmen Coulter) using a 96-well plate format. Measurements of cell viability, PDCD1 expression, GFP expression, and CAR expression were performed on 10,000 or 20,000 single cell events in Jurkat or primary T-cells, respectively.
For the cell viability and GFP knock-in measurements, approximately 250,000 cells per sample were transferred onto 96-well V-bottom cell culture plates and assessed following a series of consecutive washing and staining steps. The first step included centrifuging the cells at 300 g for 5 minutes at room temperature, discarding the supernatant, and washing cells in 150 μL Dulbecco's PBS/2% FBS (STEMCELL Technologies) or Cell Staining Buffer (Biolegend), respectively, followed by the second centrifugation and removal of supernatant. The final step included viability staining of cells using 150 μL Dulbecco's PBS/2% FBS with 7-amino-actinomycin D (7-AAD, 1:1,000; ThermoFisher) or 50 μL Cell Staining Buffer with Zombie Violet Dye (1:200; Biolegend), respectively. The measurements of cell viability and GFP expression were collected simultaneously for 7-AAD (excitation: yellow-green laser; emission: 561 nm), Zombie Violet (excitation: violet laser; emission 405 nm), and GFP (excitation: blue laser; emission 488 nm) as needed.
For detection of CAR knock-in efficiency, approx. 250,000 cells per sample were transferred onto 96-well V-bottom, washed as described above using Cell Staining Buffer, and re-suspended in 50 μL Cell Staining Buffer with PE Anti-Myc tag antibody [9E10] (1:50; Abcam) and Zombie Violet Dye (1:200; Biolegend) for 30 minutes. Afterwards, the cells were washed in two subsequent washing steps using 150 μL Cell Staining Buffer, and finally re-suspended in 100 μL Cell Staining Buffer for the flow cytometry measurements (excitation: yellow-green laser; emission: 561 nm).
For detection of PDCD1 knock-out efficiency, approx. 250,000 Jurkat cells per sample were transferred onto 96-well V-bottom cell culture plates and assessed following a series of consecutive washing and staining steps. The first step included centrifuging the cells at 300 g for 5 minutes at 4° C. and discarding the supernatant. Afterwards, the cells were stained using 100 μL Cell Staining Buffer (Biolegend) with APC/Cyanine7 anti-human CD279 (PD-1) antibody (1:100; Biolegend) and incubated for 30 minutes at 4° C. in the dark. The cells were then centrifuged at 300 g for 5 minutes at 4° C. and the supernatant discarded. The next step included two repeats of centrifugation at 300 g for 5 minutes at 4° C., supernatant removal, and cell washing in 150 μL ice-cold Cell Staining Buffer (Biolegend). In the final step, the cells were re-suspended in 100 μL Cell Staining Buffer for the flow cytometry measurements (excitation: red laser; emission: 633 nm).
Example 8: DNA Extraction Cells were harvested 48-h post-transfection by centrifugation (1,000 g, 10 minutes) in 96-well, V-bottom plates (Greiner), washed with PBS (Sigma Aldrich) and lysed in 20 μL QuickExtract DNA Extraction Solution (Epicentre, Lucigen). DNA was extracted following the manufacturer's protocol: 15 minutes at 65° C., 15 minutes at 68° C., 10 minutes at 95° C., cooled to 4° C., and stored at 4° C. Genomic DNA was diluted 20-fold in nuclease-free water before amplicon PCR reactions.
Example 9: Amplicon Sequencing Extracted genomic DNA was quantified using the NanoDrop (ThermoFisher Scientific). Amplicons were constructed in two PCR steps: in the first PCR, regions of interest (150-400 bp) were amplified from 10 to 30 ng of genomic DNA with primers containing Illumina forward and reverse adapters on both ends comprising suitable loci-specific complementary sequences, using Phusion High-Fidelity PCR Master Mix (ThermoFisher Scientific). Amplification products were purified with Agencourt AMPure XP beads (Ramcon), using the sample to beads ratio of 1:1.8. The DNA was eluted from the beads with nuclease-free water and the size of the purified amplicons analyzed on a 2% agarose E-gel using the E-gel electrophoresis system (ThermoFisher Scientific). In the second PCR, unique pairs of Illumina-compatible indexes (Nextera XT Index Kit v2) were added to the amplicons using the KAPA HiFi HotStart Ready Mix (Roche). The amplified products were purified with Agencourt AMPure XP beads (Ramcon), using the sample to bead ratio of 1:1.8. The DNA was eluted from the beads with 10 mM Tris-HCl pH 8.5, 0.1% Tween 20. Sizes of the purified DNA fragments were validated on a 2% agarose gel using the E-gel electrophoresis system (ThermoFisher Scientific), quantified using Qubit dsDNA HS Assay Kit (Thermo Fisher) and then pooled in equimolar concentrations. Quality of the amplicon library was validated using Bioanalyzer, High Sensitivity DNA Kit (Agilent) before sequencing. The final library was sequenced on Illumina MiSeq System using the MiSeq Reagent Kit v.2 (300 cycles, 2×250 bp, paired-end reads). De-multiplexed FASTQ files were obtained from BaseSpace (Illumina).
Example 10: NGS Data Analysis Initial quality assessment of the obtained reads was performed with FastQC36. The sequencing data were aligned and analyzed with the CRISPResso2 software, using CRISPRessoBatch command with the parameters—cleavage_offset 1—quantification_window_size 10—quantification_window_center 1—expand_ambiguous_alignments for the INDEL frequency analysis. For the ORF disruption analysis, CRISPRessoBatch command with the parameters—cleavage_offset 1—coding_seq <EXON_SEQ>—quantification_window_size 0—quantification_window_center 1—expand_ambiguous_alignments was used. Modification rates from the CRISPResso2 software output were analyzed in Excel.
Example 11: CRISPR-MAD7 Platform for Human Genome Editing Using the Jurkat T-Cell Leukemia Line MAD7 nuclease comprising a His6 tag (SEQ ID NO: 423) and either one (MAD7-1NLS) or four (MAD7-4NLS) nuclear localization signals (NLS) were used (FIG. 1). RNPs were generated as described in Example 3. Editing frequency of the MAD7 nuclease complexed with one or more guide nucleic acids comprising a spacer sequence of SEQ ID NOs: 86-384 as shown in Table 1 was determined by nucleofection of RNPs in Jurkat T-cells using the Lonza recommended nucleofection program SE-CL-120 (Example 5), followed by genomic DNA extraction (Example 8), amplification of the edited locus and targeted next-generation sequencing (Example 9) for identification of the edits, and finally by computational analysis (Example 10) of modification frequency using the CRISPResso2 algorithm.
TABLE 1
Spacer sequences
Name PAM SEQ ID NO Spacer sequence
crCD247_1 TTTC 114 ACCGCGGCCAUCCUGCAGGCA
crCD247_2 TTTC 115 UGAGGGAAAGGACAAGAUGAA
crCD247_3 TTTG 116 GGAUCCAGCAGGCCAAAGCUC
crCD247_4 TTTC 117 CUAGCAGAGAAGGAAGAACCC
crCD247_5 TTTC 118 UGUGUUGCAGUUCAGCAGGAG
crCD247_6 CTTC 119 CUGAGGGUUCUUCCUUCUCUG
crCD247_7 CTTC 120 CCGUUGUCUUUCCUAGCAGAG
crCD247_8 TTTC 121 UGCAGUUCCUGCAGAAGAGGG
crCD247_9 CTTC 122 UGCAGGAACUGCAGAAAGAUA
crCD247_10 TTTC 123 AUCCCAAUCUCACUGUAGGCC
crCD247_11 CTTT 124 CAUCCCAAUCUCACUGUAGGC
crCD247_12 TTTT 125 CUCAUUUCACUCCCAAACAAC
crCD247_13 TTTC 126 UCAUUUCACUCCCAAACAACC
crCD247_14 TTTC 127 ACUCCCAAACAACCAGCGCCG
crCD247_15 CTTA 128 CGUUAUAGAGCUGGUUCUGGC
crCD247_16 TTTG 129 UUUUCUGAUUUGCUUUCACGC
crCD247_17 TTTC 130 UGAUUUGCUUUCACGCCAGGG
crCD247_18 TTTG 131 CUUUCACGCCAGGGUCUCAGU
crCD247_19 TTTC 132 ACGCCAGGGUCUCAGUACAGC
crCD247_20 TTTC 133 CGGAGGGUCUACGGCGAGGCU
crCD247_21 TTTC 134 UUAUCUGUUAUAGGAGCUCAA
crCD247_22 CTTA 135 UCUGUUAUAGGAGCUCAAUCU
crCD247_23 CTTG 136 UCCAAAACAUCGUACUCCUCU
crCD247_24 TTTC 137 CCCCCAUCUCAGGGUCCCGGC
crCD247_25 TTTG 138 GACAAGAGACGUGGCCGGGAC
crCD247_26 TTTC 139 UCUCCCUCUAACGUCUUCCCG
crCTLA4_1 TTTG 140 CCUGGAGAUGCAUACUCACAC
crCTLA4_2 TTTG 141 CAGAAGACAGGGAUGAAGAGA
crCTLA4_3 TTTC 142 CACUGGAGGUGCCCGUGCAGA
crCTLA4_4 TTTG 143 UGUGUGAGUAUGCAUCUCCAG
crCTLA4_5 TTTC 144 AGCGGCACAAGGCUCAGCUGA
crCTLA4_6 CTTG 145 UGCCGCUGAAAUCCAAGGCAA
crCTLA4_7 CTTT 146 UCCAUGCUAGCAAUGCACGUG
crCTLA4_8 TTTT 147 CCAUGCUAGCAAUGCACGUGG
crCTLA4_9 CTTT 148 GUGUGUGAGUAUGCAUCUCCA
crCTLA4_10 CTTT 149 GCCUGGAGAUGCAUACUCACA
crCTLA4_11 CTTC 150 GGCAGGCUGACAGCCAGGUGA
crCTLA4_12 CTTC 151 AGUCACCUGGCUGUCAGCCUG
crCTLA4_13 CTTC 152 CUAGAUGAUUCCAUCUGCACG
crCTLA4_14 CTTG 153 CCUUGGAUUUCAGCGGCACAA
crCTLA4_15 CTTG 154 AUUUCCACUGGAGGUGCCCGU
crCTLA4_16 CTTG 155 GAUAGUGAGGUUCACUUGAUU
crCTLA4_17 CTTG 156 CAGAUGUAGAGUCCCGUGUCC
crCTLA4_18 TTTG 157 CUCACCAAUUACAUAAAUCUG
crCTLA4_19 CTTT 158 GCUCACCAAUUACAUAAAUCU
crCTLA4_20 CTTT 159 GUUUUCUGUUGCAGAUCCAGA
crCTLA4_21 TTTG 160 UUUUCUGUUGCAGAUCCAGAA
crCTLA4_22 TTTT 161 CUGUUGCAGAUCCAGAACCGU
crCTLA4_23 CTTC 162 CUCCUCUGGAUCCUUGCAGCA
crCTLA4_24 CTTG 163 CAGCAGUUAGUUCGGGGUUGU
crCTLA4_25 CTTG 164 GAUUUCAGCGGCACAAGGCUC
crCTLA4_26 TTTT 165 UUUAUAGCUUUCUCCUCACAG
crCTLA4_27 CTTT 166 CUCCUCACAGCUGUUUCUUUG
crCTLA4_28 TTTC 167 UCCUCACAGCUGUUUCUUUGA
crCTLA4_29 TTTT 168 GCUCAAAGAAACAGCUGUGAG
crCTLA4_30 TTTC 169 UUUUUGUGUUUGACAGCUAAA
crCTLA4_31 TTTT 170 UGUGUUUGACAGCUAAAGAAA
crCTLA4_32 TTTG 171 ACAGCUAAAGAAAAGAAGCCC
crCTLA4_33 TTTT 172 CACAUAGACCCCUGUUGUAAG
crCTLA4_34 TTTT 173 CACAUUCUGGCUCUGUUGGGG
crCTLA4_35 CTTT 174 UCACAUUCUGGCUCUGUUGGG
crCTLA4_36 TTTC 175 AGCCUUAUUUUAUUCCCAUCA
crCTLA4_37 TTTC 176 UCAAUUGAUGGGAAUAAAAUA
crCTLA4_38 TTTT 177 UUCUUCUCUUCAUCCCUGUCU
crCTLA4_39 CTTT 178 GCAGAAGACAGGGAUGAAGAG
crCTLA4_40 CTTT 179 GGCUUUUCCAUGCUAGCAAUG
crCTLA4_41 TTTG 180 GCUUUUCCAUGCUAGCAAUGC
crLAG3_1 TTTG 181 GGGUGCAUACCUGUCUGGCUG
crLAG3_2 TTTG 182 GGUCACCUGGAUCCCUGGGGA
crLAG3_3 TTTC 183 UCAGGACCUUGGCUGGAGGCA
crLAG3_4 TTTC 184 CCAGCCUUGGCAAUGCCAGCU
crLAG3_5 TTTG 185 UGAGGUGACUCCAGUAUCUGG
crLAG3_6 CTTG 186 CUGUUUCUGCAGCCGCUUUGG
crLAG3_7 CTTG 187 CACAGUGACUGCCAGCCCCCC
crLAG3_8 TTTT 188 GAACUGCUCCUUCAGCCGCCC
crLAG3_9 CTTC 189 AGCCGCCCUGACCGCCCAGCC
crLAG3_10 TTTC 190 CGCUAAGUGGUGAUGGGGGGA
crLAG3_11 CTTT 191 CCGCUAAGUGGUGAUGGGGGG
crLAG3_12 CTTA 192 GCGGAAAGCUUCCUCUUCCUG
crLAG3_13 CTTG 193 GGGCAGGAAGAGGAAGCUUUC
crLAG3_14 CTTC 194 CUCUUCCUGCCCCAAGUCAGC
crLAG3_15 CTTC 195 AACGUCUCCAUCAUGUAUAAC
crLAG3_16 TTTT 196 CUUUUCUCUUCAGGUCUGGAG
crLAG3_17 TTTC 197 UGCAGCCGCUUUGGGUGGCUC
crLAG3_18 TTTT 198 CUCUUCAGGUCUGGAGCCCCC
crLAG3_19 CTTG 199 ACAGUGUACGCUGGAGCAGGU
crLAG3_20 CTTG 200 GCAGUGAGGAAAGACCGGGUC
crLAG3_21 TTTC 201 CUCACUGCCAAGUGGACUCCU
crLAG3_22 CTTT 202 ACCCUUCGACUAGAGGAUGUG
crLAG3_23 TTTA 203 CCCUUCGACUAGAGGAUGUGA
crLAG3_24 CTTC 204 GACUAGAGGAUGUGAGCCAGG
crLAG3_25 TTTC 205 CCACCUGAGGCUGACCUGUGA
crLAG3_26 CTTT 206 CCCACCUGAGGCUGACCUGUG
crLAG3_27 CTTC 207 UACUCUUUUCAGUGACUCCCA
crLAG3_28 TTTT 208 ACCUGGAGCCACCCAAAGCGG
crLAG3_29 TTTT 209 CAGUGACUCCCAAAUCCUUUG
crLAG3_30 CTTC 210 CCCAGGGAUCCAGGUGACCCA
crLAG3_31 CTTT 211 GGGUCACCUGGAUCCCUGGGG
crLAG3_32 CTTT 212 GUGAGGUGACUCCAGUAUCUG
crLAG3_33 CTTT 213 GUGUGGAGCUCUCUGGACACC
crLAG3_34 TTTG 214 UGUGGAGCUCUCUGGACACCC
crLAG3_35 CTTG 215 GCUGGAGGCACAGGAGGCCCA
crLAG3_36 TTTT 216 GCUCACCUAGUGAAGCCUCUC
crLAG3_37 CTTT 217 CCCAGCCUUGGCAAUGCCAGC
crLAG3_38 CTTG 218 GCAAUGCCAGCUGUACCAGGG
crLAG3_39 CTTC 219 UUGGAGCAGCAGUGUACUUCA
crLAG3_40 CTTC 220 ACAGAGCUGUCUAGCCCAGGU
crLAG3_41 CTTT 221 CUCCAUAGGUGCCCAACGCUC
crLAG3_42 TTTC 222 UCCAUAGGUGCCCAACGCUCU
crLAG3_43 TTTC 223 UCAUCCUUGGUGUCCUUUCUC
crLAG3_44 CTTG 224 GUGUCCUUUCUCUGCUCCUUU
crLAG3_45 CTTT 225 CUCUGCUCCUUUUGGUGACUG
crLAG3_46 CTTC 226 UGCGAAGAGCAGGGGUCACUU
crLAG3_47 CTTT 227 UGGUGACUGGAGCCUUUGGCU
crLAG3_48 TTTT 228 GGUGACUGGAGCCUUUGGCUU
crLAG3_49 CTTT 229 GGCUUUCACCUUUGGAGAAGA
crLAG3_50 TTTG 230 GCUUUCACCUUUGGAGAAGAC
crLAG3_51 CTTG 231 CUCUAAGGCAGAAAAUCGUCU
crLAG3_52 TTTT 232 CUGCCUUAGAGCAAGGGAUUC
crLAG3_53 CTTA 233 GAGCAAGGGAUUCACCCUCCG
crLAG3_54 TTTC 234 CCGCCCAGUGGCCCGCCCGCU
crLAG3_55 CTTC 235 UCGCUAUGGCUGCGCCCAGCC
crLAG3_56 TTTA 236 UCCUUGCACAGUGACUGCCAG
crPDCD1_1 TTTA 237 GCACGAAGCUCUCCGAUGUGU
crPDCD1_2 TTTC 238 UCUGCAGGGACAAUAGGAGCC
crPDCD1_3 TTTC 239 CAGUGGCGAGAGAAGACCCCG
crPDCD1_4 TTTC 240 CUAGCGGAAUGGGCACCUCAU
crPDCD1_5 CTTC 241 GUGCUAAACUGGUACCGCAUG
crPDCD1_6 CTTC 242 AACCUGACCUGGGACAGUUUC
crPDCD1_7 CTTG 243 UCCGUCUGGUUGCUGGGGCUC
crPDCD1_8 CTTC 244 CCCGAGGACCGCAGCCAGCCC
crPDCD1_9 CTTC 245 CGUGUCACACAACUGCCCAAC
crPDCD1_10 CTTC 246 CACAUGAGCGUGGUCAGGGCC
crPDCD1_11 CTTT 247 GAUCUGCGCCUUGGGGGCCAG
crPDCD1_12 TTTG 248 AUCUGCGCCUUGGGGGCCAGG
crPDCD1_13 CTTG 249 GGGGCCAGGGAGAUGGCCCCA
crPDCD1_14 CTTT 250 GUGCCCUUCCAGAGAGAAGGG
crPDCD1_15 TTTG 251 UGCCCUUCCAGAGAGAAGGGC
crPDCD1_16 TTTC 252 CCUUCCGCUCACCUCCGCCUG
crPDCD1_17 CTTC 253 CAGAGAGAAGGGCAGAAGUGC
crPDCD1_18 CTTC 254 UGCCCUUCUCUCUGGAAGGGC
crPDCD1_19 TTTG 255 GAACUGGCCGGCUGGCCUGGG
crPDCD1_20 CTTT 256 CUCCUCAAAGAAGGAGGACCC
crPDCD1_21 TTTC 257 UCCUCAAAGAAGGAGGACCCC
crPDCD1_22 CTTC 258 UCUCGCCACUGGAAAUCCAGC
crPDCD1_23 CTTT 259 CCUAGCGGAAUGGGCACCUCA
crPDCD1_24 CTTC 260 CGCUCACCUCCGCCUGAGCAG
crPDCD1_25 CTTG 261 GCCCCUCUGACCGGCUUCCUU
crPDCD1_26 CTTC 262 UCCACUGCUCAGGCGGAGGUG
crPDCD1_27 CTTC 263 UCCCCAGCCCUGCUCGUGGUG
crPDCD1_28 CTTC 264 GGUCACCACGAGCAGGGCUGG
crPDCD1_29 CTTC 265 ACCUGCAGCUUCUCCAACACA
crPDCD1_30 CTTC 266 UCCAACACAUCGGAGAGCUUC
crPTPN1_1 TTTA 267 CCUGACAGCGAAUCAUAACAU
crPTPN1_2 TTTC 268 AUUCCAACUUACCUAACGGAA
crPTPN1_3 TTTC 269 UGUGCGCACUGGUGAUGACAA
crPTPN11_4 TTTC 270 CAAUCUGCUCACCUGCUUGAG
crPTPN11_5 TTTC 271 UUCUAGUUGAUCAUACCAGGG
crPTPN11_6 TTTA 272 AUAACUUACCUCAAAUUCUUC
crPTPN11_7 CTTA 273 CCUAACGGAAAGUGUGAAGUC
crPTPN11_8 TTTC 274 CAGACACUACAACAACAGGAG
crPTPN11_9 TTTA 275 GGUGGUUUCAUGGACAUCUCU
crPTPN11_10 TTTC 276 CCAGAGAGAUGUCCAUGAAAC
crPTPN6_1 TTTC 277 UAUGACCUGUAUGGAGGGGAG
crPTPN6_2 TTTG 278 CGACUCUGACAGAGCUGGUGG
crPTPN6_3 TTTG 279 CAGAAGCAGGAGGUGAAGAAC
crPTPN6_4 TTTG 280 ACUGCCCCCCACCCAGGCCUG
crPTPN6_5 CTTA 281 UGGGCCCUACUCUGUGACCAA
crPTPN6_6 TTTC 282 ACCGAGACCUCAGUGGGCUGG
crPTPN6_7 CTTC 283 UCUAGGUGGUACCAUGGCCAC
crPTPN6_8 CTTG 284 GCCUGCAGCAGCGUCUCUGCC
crPTPN6_9 TTTC 285 UUGUGCGUGAGAGCCUCAGCC
crPTPN6_10 CTTC 286 GUGCUUUCUGUGCUCAGUGAC
crPTPN6_11 CTTG 287 GGCUGGUCACUGAGCACAGAA
crPTPN6_12 CTTT 288 CUGUGCUCAGUGACCAGCCCA
crPTPN6_13 TTTC 289 UGUGCUCAGUGACCAGCCCAA
crPTPN6_14 CTTG 290 AUGUGGGUGACCCUGAGCGGG
crPTPN6_15 CTTA 291 CCUCGCACAUGACCUUGAUGU
crPTPN6_16 TTTG 292 GCUCCCCCCAGGGUGGACGCU
crPTPN6_17 CTTG 293 AGCAGGGUCUCUGCAUCCAGC
crPTPN6_18 TTTG 294 GAGACCUUCGACAGCCUCACG
crPTPN6_19 CTTC 295 GACAGCCUCACGGACCUGGUG
crPTPN6_20 TTTC 296 AAGAAGACGGGGAUUGAGGAG
crPTPN6_21 CTTC 297 UUGUUCAGUUCCAACACUCGG
crPTPN6_22 CTTG 298 GCUGUAUCCUCGGACUCCUGC
crPTPN6_23 TTTC 299 CCCACCCACAUCUCAGAGUUU
crPTPN6_24 CTTC 300 CAGACGCUGGUGCAAGUUCUU
crPTPN6_25 CTTG 301 CACCAGCGUCUGGAAGGGCAG
crPTPN6_26 CTTG 302 UUCUCUGGCCGCUGCCCUUCC
crPTPN6_27 CTTG 30 AUGUAGUUGGCAUUGAUGUAG
crPTPN6_28 CTTG 304 CGUCCAGAACCAGCUGCUAGG
crPTPN6_29 CTTC 305 UGGCAGAUGGCGUGGCAGGAG
crPTPN6_30 TTTC 306 UCCACCUCUCGGGUGGUCAUG
crPTPN6_31 CTTT 307 CUCCACCUCUCGGGUGGUCAU
crPTPN6_32 CTTT 308 CCAGAACAAAUGCGUCCCAUA
crPTPN6_33 TTTC 309 CAGAACAAAUGCGUCCCAUAC
crPTPN6_34 TTTG 310 UAUUCGGUUGUGUCAUGCUCC
crPTPN6_35 CTTA 311 CAGGUCUCCCCGCUGGACAAU
crPTPN6_36 CTTC 312 CUGGCUCGGCCCAGUCGCAAG
crPTPN6_37 CTTA 313 GGGAGACCUGAUUCGGGAGAU
crPTPN6_38 CTTC 314 CUGGACCAGAUCAACCAGCGG
crPTPN6_39 TTTC 315 CUGCCGCUGGUUGAUCUGGUC
crPTPN6_40 CTTT 316 CCUGCCGCUGGUUGAUCUGGU
crPTPN6_41 CTTG 317 GUGGAGAUGUUCUCCAUGAGC
crPTPN6_42 CTTG 318 UACUGCGCCUCCGUCUGCACC
crPTPN6_43 TTTC 319 AAUGAACUGGGCGAUGGCCAC
crPTPN6_44 CTTC 320 UUCUUAGUGGUUUCAAUGAAC
crPTPN6_45 CTTC 321 UCCCCUCCAUACAGGUCAUAG
crPTPN6_46 CTTG 322 GAGUCUAGUGCAGGGACCGUG
crPTPN6_47 CTTG 323 CCCCCCUGCACCCGGCUGCAG
crPTPN6_48 CTTG 324 UGUCUGCAGCCGGGUGCAGGG
crPTPN6_49 TTTC 325 UCCUCCCUCUUGUUCUUAGUG
crPTPN6_50 CTTT 326 CUCCUCCCUCUUGUUCUUAGU
crPTPN6_51 CTTC 327 UUCACUUUCUCCUCCCUCUUG
crPTPN6_52 CTTG 328 AGGUGGAUGAUGGUGCCGUCG
crPTPN6_53 CTTC 329 CCUGACGCUGCCUUCUCUAGG
crTIGIT_1 TTTC 330 AGGCCUUACCUGAGGCGAGGG
crTIGIT_2 TTTT 331 GUCCUCCCUCUAGUGGCUGAG
crTIGIT_3 CTTG 332 GGGUGGCACAUCUCCCCAUCC
crTIGIT_4 TTTC 333 UGCAGAGAAAGGUGGCUCUAU
crTIGIT_5 TTTG 334 UAAUGCUGACUUGGGGUGGCA
crTIGIT_6 CTTA 335 CCUGAGGCGAGGGGAGCCUGC
crTIGIT_7 CTTG 336 AAGGAUGGGGAGAUGUGCCAC
crTIGIT_8 CTTC 337 AAGGAUCGAGUGGCCCCAGGU
crTIGIT_9 CTTC 338 UGCAUCUAUCACACCUACCCU
crTIGIT_10 TTTC 339 UAGGACCUCCAGGAAGAUUCU
crTIGIT_11 CTTT 340 CUAGGACCUCCAGGAAGAUUC
crTIGIT_12 CTTG 341 CUCCAGCAGGAAUACCUGAGC
crTIGIT_13 CTTG 342 GAGCCAUGGCCGCGACGCUGG
crTIGIT_14 TTTC 343 UAGUCAACGCGACCACCACGA
crTIGIT_15 CTTT 344 CUAGUCAACGCGACCACCACG
crTIGIT_16 TTTG 345 UAGUUUGUUUGUUUUUAGAAG
crTIGIT_17 TTTG 346 UUUGUUUUUAGAAGAAAGCCC
crTIGIT_18 TTTG 347 UUUUUAGAAGAAAGCCCUCAG
crTIGIT_19 TTTT 348 UAGAAGAAAGCCCUCAGAAUC
crTIGIT_20 CTTC 349 CACAGAAUGGAUUCUGAGGGC
crTIGIT_21 TTTT 350 CUCCUGAGGUCACCUUCCACA
crTIGIT_22 CTTC 351 CUGGGGGUGAGGGAGCACUGG
crTIGIT_23 CTTC 352 UGCCUGGACACAGCUUCCUGG
crTIGIT_24 CTTC 353 GUCCUCUUCCCUAGGAAUGAU
crTIGIT_25 CTTC 354 UGUAACUCAGGACAUUGAAGU
crTIGIT_26 CTTC 355 AAUGUCCUGAGUUACAGAAGC
crTIGIT_27 TTTC 356 UAUUGUGCCUGUCAUCAUUCC
crTIGIT_28 TTTC 357 UCUGCAGAAAUGUUCCCCGUU
crTIGIT_29 CTTT 358 CUCUGCAGAAAUGUUCCCCGU
crTIGIT_30 CTTG 359 UGCCGUGGUGGAGGAGAGGUG
crTIGIT_31 CTTC 360 UGGCCAUUUGUAAUGCUGACU
crTIM3_1 CTTA 361 CUUGUAAGUAGUAGCAGCAGC
crTIM3_2 TTTC 362 CAAGGAUGCUUACCACCAGGG
crTIM3_3 CTTG 363 UAAGUAGUAGCAGCAGCAGCA
crTIM3_4 CTTA 364 CCACCAGGGGACAUGGCCCAG
crTIM3_5 TTTG 365 AAUGUGGCAACGUGGUGCUCA
crTIM3_6 CTTT 366 UCUUCUGCAAGCUCCAUGUUU
crTIM3_7 CTTT 367 GCCCCAGCAGACGGGCACGAG
crTIM3_8 TTTC 368 AUCAGUCCUGAGCACCACGUU
crTIM3_9 CTTT 369 CAUCAGUCCUGAGCACCACGU
crTIM3_10 TTTA 370 GCCAGUAUCUGGAUGUCCAAU
crTIM3_11 TTTG 371 CGGAAAUCCCCAUUUAGCCAG
crTIM3_12 CTTT 372 GCGGAAAUCCCCAUUUAGCCA
crTIM3_13 TTTC 373 CGCAAAGGAGAUGUGUCCCUG
crTIM3_14 TTTG 374 GAUCCGGCAGCAGUAGAUCCC
crTIM3_15 TTTT 375 UCAUCAUUCAUUAUGCCUGGG
crTIM3_16 TTTT 376 CUUCUGCAAGCUCCAUGUUUU
crTIM3_17 CTTC 377 AGGUUAAAUUUUUCAUCAUUC
crTIM3_18 TTTG 378 AUGACCAACUUCAGGUUAAAU
crTIM3_19 TTTA 379 ACCUGAAGUUGGUCAUCAAAC
crTIM3_20 CTTA 380 UGUUGUUUCUGACAUUAGCCA
crTIM3_21 TTTC 381 UGACAUUAGCCAAGGUCACCC
crTIM3_22 CTTG 382 GAAAGGCUGCAGUGAAGUCUC
crTIM3_23 CTTC 383 ACUGCAGCCUUUCCAAGGAUG
crTIM3_24 CTTT 384 CCAAGGAUGCUUACCACCAGG
crTIM3_25 TTTT 385 CACAUCUUCCCUUUGACUGUG
crTIM3_26 TTTT 386 UAUAGCAGAGACACAGACACU
crTIM3_27 TTTA 387 UAUCAGGGAGGCUCCCCAGUG
crTIM3_28 CTTA 388 CUGUUAGAUUUAUAUCAGGGA
crTIM3_29 TTTG 389 UGUUUCCAUAGCAAAUAUCCA
crTIM3_30 TTTC 390 CAUAGCAAAUAUCCACAUUGG
crTIM3_31 CTTA 391 CGGGACUCUGGAGCAACCAUC
crTIM3_32 TTTG 392 AAAAUUAAAGCGCCGAAGAUA
crTIM3_33 CTTA 393 CAUUUGAAAAUUAAAGCGCCG
crTIM3_34 CTTT 394 UGUUUCCCCCUUACUAGGGUA
crTIM3_35 TTTT 395 GUUUCCCCCUUACUAGGGUAU
crTIM3_36 CTTT 396 GACUGUGUCCUGCUGCUGCUG
crTIM3_37 TTTC 397 CCCCUUACUAGGGUAUUCUCA
crTIM3_38 CTTA 398 CUAGGGUAUUCUCAUAGCAAA
crTIM3_39 CTTA 399 AAUUCUGUAUCUUCUCUUUGC
crTIM3_40 CTTT 400 AUUUCCACAGCCUCAUCUCUU
crTIM3_41 TTTA 401 UUUCCACAGCCUCAUCUCUUU
crTIM3_42 TTTC 402 CACAGCCUCAUCUCUUUGGCC
crTIM3_43 TTTG 403 GCCAACCUCCCUCCCUCAGGA
crTIM3_44 TTTG 404 CCAAUCCUGAGGGAGGGAGGU
crTIM3_45 TTTT 405 CUUCUGAGCGAAUUCCCUCUG
crTIM3_46 CTTC 406 AUAUACGUUCUCUUCAAUGGU
crTIM3_47 CTTT 407 GGGUUGUCGCUUUGCAAUGCC
crTIM3_48 TTTG 408 GGUUGUCGCUUUGCAAUGCCA
crTIM3_49 CTTC 409 UCUCUCUAUGCAGGGUCCUCA
crTIM3_50 CTTC 410 UACACCCCAGCCGCCCCAGGG
crTIM3_51 TTTG 411 CCCCAGCAGACGGGCACGAGG
crAAVS1 TTTC 412 TTAGGATGGCCTTCTCCGACG
Firstly, using a gNA targeting the DNMT1 locus, the editing frequency of MAD7 comprising either one or four NLS complexed with the respective gNA was compared. RNP concentration-dependent modification efficiency was observed as evidenced by an increased fraction of modified amplicons (FIG. 2, left axis, dark grey for MAD7-1NLS and light grey representing MAD7-4NLS). Error bars represent one standard deviation for a sample of 3 (n=3). In this experiment, editing frequency was enhanced in Jurkat cells when treated with RNPs comprising MAD-4NLS, which indicates that optimization of the NLS can improve editing efficiency. A slight decrease in cell viability was seen at higher concentrations of RNP for those comprising four NLS as compared to one NLS (FIG. 2, right axis). Specifically, FIG. 2 shows editing frequency at the DNMT1 locus (n=3; Mean±SD) and cell viability of T-cell leukemic cells as a function of MAD7 comprising one or four nuclear localization signal (NLS) and MAD7-RNP amounts (pmol; constant ratio of 1:1.5 MAD7:gNA). Dark grey bars and circles represent mean modification frequency and viability using MAD7-1NLS, respectively. Light grey bars and triangles represent mean modification frequency and viability using MAD7-4NLS, respectively.
To optimize editing activity, 93 different transfection conditions were tested; 31 nucleofection programs in combination with three buffers—on the Lonza Nucleofector 96-well Shuttle System (FIGS. 3-5). FIGS. 3, 4, and 5 show the editing frequency (bars; x-axis) of each of the electroporation conditions (buffers SE, SF, and SG respectively) as compared to a control (y-axis, control at the top). The majority of buffer-program transfection combinations resulted in suboptimal viability (dots; x-axis) and editing frequency, however, the analysis revealed several conditions that supported substantial rates of both cell viability and editing. Two improved conditions observed in the screen, namely SF-CA-137 and SG-CA-138, were then validated and compared to the Lonza recommended nucleofection programs for T-cell leukemia, namely SE-CL-120 and SE-CK-116 (FIG. 6). Specifically, FIG. 6 shows editing frequency at the DNMT1 locus (n=4; Mean±SD) in T-cell leukemic cell line achieved by utilization of the transfection conditions identified in FIG. 2 (100 pmol MAD7-4NLS) and Lonza recommended nucleofection programs SE-CK-116 and SE-CL-120, as well as the two best nucleofection programs observed in this study, SF-CA-137 and SG-CA-138 (FIGS. 3-5). Dark grey bars represent mean modification frequency using crDNMT1. Light grey bars represent mean modification frequency using crIDTneg (Integrated DNA Technologies, IDT).
Example 12: Scalable High-Level MAD7-RNP Editing of Immunologically Relevant Genes in Jurkate T-Cell Leukemia Cell Line The Jurkat T-cell leukemia cell line was used as a model system to screen GNAs demonstrating high editing efficiency. The screen included 298 unique gNAs comprising one or more spacer sequences of SEQ ID NOs: 86-384 of Table 1 targeting the immune checkpoint receptors PDCD1, TIM3, LAG3, TIGIT, and CTLA4, the checkpoint phosphatases PTPN6 (SHP-1) and PTPN11 (SHP-2), and the TCR signaling subunit CD247 (CD3ζ). RNPs were generated as described in Example 3, nucleofected (Example 5), genomic DNA was extracted (Example 8), the edited loci amplified and sequenced (Example 9), and the sequencing data computationally analyzed (Example 10) using the CRISPResso2 algorithm.
CRISPResso2 software reports the frequency of modifications (insertions, deletions, and substitutions) within a quantification window flanking the position of MAD7-induced cleavage in the amplicon sequence. To better understand detection of editing events, the type of modifications detected in 230 amplicons that were sequenced in both gNA-treated and MOCK samples (no MAD7) were compared. Relatively high modification frequencies (median 1%) in MOCK reactions were observed as a result of high frequency of substitutions (FIG. 7, light grey bars); substitutions were detected at a median frequency of 0.96%, likely due to the errors in NGS base calling or substitutions arising during DNA amplification, while insertions and deletions were found at a much lower median frequency of 0.003% and 0.042%, respectively. Specifically, FIG. 7 shows editing frequency at eight different loci using 298 gNAs (n=3; Mean±SD) in T-cell leukemic cell line as a function of various editing types: all modifications, only insertions, only deletions, only substitutions, or insertions and deletions (INDELs). Edits were achieved using the transfection conditions identified in Example 11, FIG. 2 (100 pmol MAD7-4NLS) and one of the tested Lonza nucleofection programs (FIG. 6; SF-CA-137). Dark grey boxplots represent mean modification frequency using gNAs. Light grey boxplots represent mean modification frequency using crIDTneg (IDT). Thus, the frequency of both insertions and deletions (INDEL) were used as a means to quantify the editing activity of the CRISPR-MAD7 system to minimize low end noise. Moreover, low INDEL frequencies in MOCK reactions enabled sensitive detection of editing events at a significantly greater fraction of sites (Fisher exact test, P=3×10−12; FIG. 8). Analysis of gNAs with low INDEL frequencies showed statistically significant editing in gNA-treated samples compared to MOCK samples at INDEL frequencies as low as 0.5% (Fisher exact test, P=4×10−8; FIG. 8). This indicates the sensitivity of the assay to detect modifications in the sub-1% range. Specifically, FIG. 8 shows INDEL frequency at eight different loci using 298 gNAs (n=3; Mean±SD) in T-cell leukemic cell line as a function of two modification types: all modifications <1%, and INDELs <1%, or <0.5%, or <0.1%, with lower INDEL frequencies in MOCK compared to gNA reactions at INDELs <1% (Fisher's exact test; P=3×10−12) and <0.5% (Fisher exact test, P=4×10−8). Dark grey boxplots represent mean INDEL frequency using gNAs. Light grey boxplots represent mean INDEL frequency using crIDTneg (IDT).
Since MAD7 can target a wide range of PAM, gNAs adjacent to all YTTN PAM variants were screened and editing specificity of MAD7 in Jurkat cells was analyzed. MAD7 demonstrated editing with all eight combinations of YTTN PAM; in this experiment, editing was higher at the YTTV and TTTV consensus sequences (Fisher exact test; P=2×10−3 and P=2×10−4, respectively). While the majority of highly-active (>50% INDEL frequency) gNAs were found at sites with YTTV and TTTV PAMs, moderately-active (>10% INDEL frequency) gNAs were found to target every PAM sequence with the exception of CTTT. This indicates that MAD7 can edit a wide range of target PAMs, albeit at reduced frequencies (FIG. 9). Specifically, FIG. 9 shows INDEL frequency at eight different loci using 298 gNAs (n=3; Mean±SD) in T-cell leukemic cell line as a function of eight YTTN PAM combinations, and TTTV, YTTN, and YTTV PAM motifs. A grey zone on the plot represents moderately-active gNAs (10-50% INDELs), the zone above highly-active gNAs (>50% INDELs), and the zone below active gNAs (1-10% INDELs). INDEL frequency at the YTTV and TTTV PAM motif is significantly higher compared to YTTN motif (Fisher exact test, P=2×10−3 and P=2×10−4, respectively).
Given the large number of gNAs analyzed, it was determined if the targeted DNA sequence biases editing efficiency. Sequence logos were made to compare the DNA-complementary gNA sequences of inactive (<1% INDELs), active (1-10% INDELs), moderately-active (10-50% INDELs), and highly-active (>50% INDELs) gNAs (FIG. 10A). While no strong biases for ribonucleotides at specific positions were identified in this experiment, guanine appeared overrepresented and uracil underrepresented on moderately-active and highly-active gNAs. Next, the frequency of ribonucleotide bases were analyzed within the same four classes of gNAs (FIG. 10B). The analysis confirmed significant enrichment of guanine and depletion of uracil on highly-active gNAs. Specifically, FIG. 10 shows (A) sequence logos comparing DNA-complementary gNA sequences of highly-active (>50% INDELs), moderately-active (10-50% INDELs), active (1-10% INDELs), and inactive (<1% INDELs) gNAs show no strong biases for ribonucleotides at specific positions, however, guanine appeared overrepresented and uracil underrepresented on highly-active and moderately-active gNAs; (B) nucleotide frequency on inactive (<1% INDELs; dark grey box), active (1-10% INDELs; medium grey box), moderately-active (10-50% INDELs; light grey box), and highly-active (>50% INDELs; white box) gNAs, with significant enrichment of guanine and depletion of uracil on highly-active gNAs compared to inactive gNAs (Fisher exact test, P=4×10−3 and P=3×10−4, respectively). Also, significant enrichment of guanine-cytosine content and depletion of adenine-uracil content was observed on moderately-active gNAs compared to inactive gNAs (Fisher exact test, P=1×10−2). Moreover, the data showed that nearly 40% of inactive gNAs had runs of three or more adenine or uracil ribonucleotides, while none of the highly-active and <20% of moderately-active gNAs contained such runs (FIG. 11). These sequence features can act as an algorithm for selecting putative high-activity gNAs during initial rounds of screening, and could reduce the overall cost of identifying gNAs for various genes of interest. Specifically, FIG. 11 shows fraction of gNAs with AAA and/or UUU runs as a function of INDEL frequency of highly-active (>50% INDELs), moderately-active (10-50% INDELs), active (1-10% INDELs), and inactive (<1% INDELs) gNAs. Fraction of inactive (<1% INDELs) and active (1-10% INDELs) gNAs containing such runs is higher compared to highly-active (>50% INDELs) gNAs (Fisher exact test, P=1×10−3 and P=4×10−4, respectively).
Example 13: Validation of gNAs for Gene Editing and Disruption of Immunologically Relevant Genes Using T-Cell Leukemia Line High-efficiency gNAs identified in our initial analysis were validated by assaying INDEL frequency for the top three or five gNAs for each of the selected immunologically relevant genes (FIG. 12). Specifically, FIG. 12 shows INDEL (dark grey bars) and frameshift (light grey bars) frequencies (n=3; Mean±SD) in T-cell leukemic cell line as a function of 38 high-efficiency gNAs. Alternating grey and white zones on the plot represent groups of three to five high-efficiency gNAs per locus. In the validation experiment, the INDEL frequency was significantly correlated to the measurements from the initial screen, highlighting the reproducibility of the INDEL assay (FIG. 13). Specifically, FIG. 13 shows correlation of INDEL frequency in the gNA validation experiment versus INDEL formation in the gNA screen experiment (Spearman's correlation=0.91; P=9×10−14), highlighting reproducibility of the INDEL assay. Using the CRISPresso2 software, the degree of open reading frame (ORF) disruption for each of the validated gNAs was estimated (FIG. 12). In addition, for four high-efficiency gNAs targeting three different exons at the PDCD1 locus, surface expression of the PDCD1 protein was measured by flow cytometry 4, 7, and 11 days post-transfection (data not shown). The data revealed that the protein surface expression after transfection with crPDCD1_2, a gNA targeting the PDCD1 gene at the extracellular domain of the protein, was as low as 10% 4 days post-transfection and remained at this level even at day 11 post-transfection. The surface expression after transfection with the remaining three gNAs was significantly higher, 35% and 85% after transfection with crPDCD1_3 and both crPDCD1_4 and crPDCD1_5, respectively. This is in line with the ORF data analysis, which showed that for most of the gNAs including the high-efficiency crPDCD1s, the predicted number of INDELs leading to frameshifts was similar to that expected from an unbiased DNA repair process, with frameshifts in two-thirds of the edited loci (FIG. 14). However, several of the gNAs had a markedly different degree of ORF disruption; crCD247_4 resulted in frameshifts with 97% frequency, while crTIM3_1 and crTIM3_3 resulted in frameshifts with 23% and 44% frequency, respectively (FIG. 14). Specifically, FIG. 14 shows fraction of frameshift to INDEL frequency (dark grey bars) in T-cell leukemic cell line as a function of 38 high-efficiency gNAs. Average fraction of INDELs leading to frameshifts (dashed line) is approx. 66%. Alternating grey and white zones on the plot represent groups of three to five high-efficiency gNAs per locus. The analysis of repair products indicates that in the case of crTIM3_1, and to some extent crTIM3_3, the bias arose from directly repeated sequences at the DNA cleavage site, which possibly promoted microhomology-mediated end joining (MMEJ) repair following DNA cleavage. These data help inform selection of gNAs for gene KO since some gNAs, such as crTIM3_1, have much lower frequency of gene disruption than would be predicted based on the frequency of INDEL formation.
Another consideration for selecting gNAs is the potential for off-target cleavage events. The list of validated gNAs was analyzed using the CasOFFinder software to predict potential off-target editing sites in the genome with up to four mismatches between the gNA and the target DNA sequence. Using the Bioconductor R packages, the predicted off-target sites were matched with the human gene database, and those sites that targeted exons and introns within the genes were extracted. Afterwards, the degree of editing activity at these sites was examined by targeted next-generation sequencing, more specifically, at 25 predicted off-target sites for the top-two PDCD1 gNAs, i.e., crPDCD1_1 and crPDCD1_2. The analysis revealed low-level off-target activity at crPDCD1_2_13 and crPDCD1_2_15 sites, however, INDEL formation at these two sites was statistically insignificant compared to MOCK samples (non-targeting gNAs) (Pairwise T-test, P≥0.05; FIGS. 15 and 16). INDEL frequency at 43 putative off-target sites with up to three mismatches between gNA and target DNA sequence were assayed for the top-two gNAs targeting seven remaining genes (i.e., TIM3, LAG3, TIGIT, CTLA4, PTPN6, PTPN11, and CD247; spacer sequences in Table 1). The analysis revealed no detectable activity at any of the putative off-target sites (FIGS. 15 and 16), which confirms the high cleavage fidelity of MAD7-gNA complexes. Specifically, FIGS. 15-16 show INDEL frequency of MAD7 (n=3; Mean±SD) in T-cell leukemic cell line at predicted off-target sites analyzed by targeted deep sequencing. For crPDCD1, INDEL frequency was analyzed at the putative off-target editing sites with ≤4 mismatches between the gNA and target DNA sequence, and with ≤3 mismatches on the remaining gNAs. PAM sequences and spacer sequences with mismatches marked in red are displayed next to their respective measured INDEL frequencies. No significant INDEL frequency at any of the off-target sites was detected (Pairwise T-test, P≥0.05).
Insertion of exogenous transgenes is an important aspect of mammalian cell engineering. Gene insertion with CRISPR-Cas is achieved by homology-directed repair of CRISPR-induced DNA breaks using HDR-donor templates to copy exogenous genetic sequences into targeted DNA loci. Several studies indicate that HDR templates, composed of linear double stranded DNA, provide the most robust and efficient method of transgene insertion using CRISPR-Cas genome editing systems.
The Jurkat T-cell leukemia cell line was used to evaluate the transgene insertion and expression efficiency using CRISPR-MAD7 RNP complexes. A highly active gNA targeting the AAVS1 (spacer sequence in Table 1) safe-harbor locus (FIG. 17) was used in combination with eight different HDR-repair templates flanked with symmetric homology arms (HA) of 500 base pairs (bp) in the amount of 0.5 μg μL−1. Specifically, FIG. 17 shows INDEL frequency at the AAVS1 locus (n=3; Mean±SD) in T-cell leukemic cell line as a function of MAD7-RNP amounts (pmol; constant ratio of 1:1.5 MAD7:gNA). Dark grey bars represent mean INDEL frequency using crAAVS1. Light grey bars represent mean modification frequency using crIDTneg (IDT). The HDR inserts comprised eight promoters (Table 2) differing in both size and promoter strength to drive GFP expression (FIG. 18). When the transient GFP expression diminished at day 14 post-transfection, comparable insertion efficiencies were observed with stable GFP expressions of up to 30% using four (JET, PGK, EF1a, and CAG) out of eight promoters (FIG. 18), suggesting that the insert size has not affected the integration efficiency at AAVS1 in human T-cell leukemia cell line. Specifically, FIG. 18 shows GFP insertion efficiency at AAVS1 (n=3; Mean±SD) and cell viability of T-cell leukemic cell line measured at day 14 post-transfection. HDR templates consisting of eight different promoters and flanked with symmetric homology arms of 500 base pairs in the amount of 0.5 μg μL−1 were used. Size of promoters in base pairs: CMV, 1400; SCP, 970; CMVe-SCP, 1270; CMVmax, 1830; JET, 1100; CAG, 2600; PGK, 1410; EF-1α, 2090. Dark grey bars and circles present mean insertion frequency and cell viability using crAAVS1. Light grey bars represent mean insertion frequency and cell viability using crIDTneg (IDT).
TABLE 2
SEQ
Name ID NO Sequence
CMV 413 CGTTACATAACTTACGGTAA
ATGGCCCGCCTGGCTGACCG
CCCAACGACCCCCGCCCATT
GACGTCAATAATGACGTATG
TTCCCATAGTAACGCCAATA
GGGACTTTCCATTGACGTCA
ATGGGTGGAGTATTTACGGT
AAACTGCCCACTTGGCAGTA
CATCAAGTGTATCATATGCC
AAGTACGCCCCCTATTGACG
TCAATGACGGTAAATGGCCC
GCCTGGCATTATGCCCAGTA
CATGACCTTATGGGACTTTC
CTACTTGGCAGTACATCTAC
GTATTAGTCATCGCTATTAC
CATGGTGATGCGGTTTTGGC
AGTACATCAATGGGCGTGGA
TAGCGGTTTGACTCACGGGG
ATTTCCAAGTCTCCACCCCA
TTGACGTCAATGGGAGTTTG
TTTTGGCACCAAAATCAACG
GGACTTTCCAAAATGTCGTA
ACAACTCCGCCCCATTGACG
CAAATGGGCGGTAGGCGTGT
ACGGTGGGAGGTCTATATAA
GCAGAGCT
SCP 414 GTACTTATATAAGGGGGTGG
GGGCGCGTTCGTCCTCAGTC
GCGATCGAACACTCGAGCCG
AGCAGACGTGCCTACGGACC
G
CMVe- 415 CGTTACATAACTTACGGTAA
SCP ATGGCCCGCCTGGCTGACCG
CCCAACGACCCCCGCCCATT
GACGTCAATAATGACGTATG
TTCCCATAGTAACGCCAATA
GGGACTTTCCATTGACGTCA
ATGGGTGGAGTATTTACGGT
AAACTGCCCACTTGGCAGTA
CATCAAGTGTATCATATGCC
AAGTACGCCCCCTATTGACG
TCAATGACGGTAAATGGCCC
GCCTGGCATTATGCCCAGTA
CATGACCTTATGGGACTTTC
CTACTTGGCAGTACATCTAC
GTATTAGTCATCGCTATTAC
CATGGTACTTATATAAGGGG
GTGGGGGCGCGTTCGTCCTC
AGTCGCGATCGAACACTCGA
GCCGAGCAGACGTGCCTACG
GACCG
CMVmax 416 TCAATATTGGCCATTAGCCA
TATTATTCATTGGTTATATA
GCATAAATCAATATTGGCTA
TTGGCCATTGCATACGTTGT
ATCTATATCATAATATGTAC
ATTTATATTGGCTCATGTCC
AATATGACCGCCATGTTGGC
ATTGATTATTGACTAGTTAT
TAATAGTAATCAATTACGGG
GTCATTAGTTCATAGCCCAT
ATATGGAGTTCCGCGTTACA
TAACTTACGGTAAATGGCCC
GCCTGGCTGACCGCCCAACG
ACCCCCGCCCATTGACGTCA
ATAATGACGTATGTTCCCAT
AGTAACGCCAATAGGGACTT
TCCATTGACGTCAATGGGTG
GAGTATTTACGGTAAACTGC
CCACTTGGCAGTACATCAAG
TGTATCATATGCCAAGTCCG
CCCCCTATTGACGTCAATGA
CGGTAAATGGCCCGCCTGGC
ATTATGCCCAGTACATGACC
TTACGGGACTTTCCTACTTG
GCAGTACATCTACGTATTAG
TCATCGCTATTACCATGGTG
ATGCGGTTTTGGCAGTACAC
CAATGGGCGTGGATAGCGGT
TTGACTCACGGGGATTTCCA
AGTCTCCACCCCATTGACGT
CAATGGGAGTTTGTTTTGGC
ACCAAAATCAACGGGACTTT
CCAAAATGTCGTAATAACCC
CGCCCCGTTGACGCAAATGG
GCGGTAGGCGTGTACGGTGG
GAGGTCTATATAAGCAGAGG
TCGTTTAGTGAACCGTCAGA
TCACTAGTAGCTTTATTGCG
GTAGTTTATCACAGTTAAAT
TGCTAACGCAGTCAGTGCTC
GACTGATCACAGGTAAGTAT
CAAGGTTACAAGACAGGTTT
AAGGAGGCCAATAGAAACTG
GGCTTGTCGAGACAGAGAAG
ATTCTTGCGTTTCTGATAGG
CACCTATTGGTCTTACTGAC
ATCCACTTTGCCTTTCTCTC
CACAGGG
JET 417 GAATTCGGGCGGAGTTAGGG
CGGAGCCAATCAGCGTGCGC
CGTTCCGAAAGTTGCCTTTT
ATGGCTGGGCGGAGAATGGG
CGGTGAACGCCGATGATTAT
ATAAGGACGCGCCGGGTGTG
GCACAGCTAGTTCCGTCGCA
GCCGGGATTTGGGTCGCGGT
TCTTGTTTGTGGATCCCTGT
GATCGTCACTTGACA
CAG 418 ATCTCGACTAGTTATTAATA
GTAATCAATTACGGGGTCAT
TAGTTCATAGCCCATATATG
GAGTTCCGCGTTACATAACT
TACGGTAAATGGCCCGCCTG
GCTGACCGCCCAACGACCCC
CGCCCATTGACGTCAATAAT
GACGTATGTTCCCATAGTAA
CGCCAATAGGGACTTTCCAT
TGACGTCAATGGGTGGAGTA
TTTACGGTAAACTGCCCACT
TGGCAGTACATCAAGTGTAT
CATATGCCAAGTACGCCCCC
TATTGACGTCAATGACGGTA
AATGGCCCGCCTGGCATTAT
GCCCAGTACATGACCTTATG
GGACTTTCCTACTTGGCAGT
ACATCTACGTATTAGTCATC
GCTATTACCATGGTCGAGGT
GAGCCCCACGTTCTGCTTCA
CTCTCCCCATCTCCCCCCCC
TCCCCACCCCCAATTTTGTA
TTTATTTATTTTTTAATTAT
TTTGTGCAGCGATGGGGGCG
GGGGGGGGGGGGGGGCGCGC
GCCAGGCGGGGCGGGGCGGG
GCGAGGGGCGGGGCGGGGCG
AGGCGGAGAGGTGCGGCGGC
AGCCAATCAGAGCGGCGCGC
TCCGAAAGTTTCCTTTTATG
GCGAGGCGGCGGCGGCGGCG
GCCCTATAAAAAGCGAAGCG
CGCGGCGGGCGGGGAGTCGC
TGCGACGCTGCCTTCGCCCC
GTGCCCCGCTCCGCCGCCGC
CTCGCGCCGCCCGCCCCGGC
TCTGACTGACCGCGTTACTC
CCACAGGTGAGCGGGCGGGA
CGGCCCTTCTCCTCCGGGCT
GTAATTAGCGCTTGGTTTAA
TGACGGCTTGTTTCTTTTCT
GTGGCTGCGTGAAAGCCTTG
AGGGGCTCCGGGAGGGCCCT
TTGTGCGGGGGGAGCGGCTC
GGGGGGTGCGTGCGTGTGTG
TGTGCGTGGGGAGCGCCGCG
TGCGGCTCCGCGCTGCCCGG
CGGCTGTGAGCGCTGCGGGC
GCGGCGCGGGGCTTTGTGCG
CTCCGCAGTGTGCGCGAGGG
GAGCGCGGCCGGGGGCGGTG
CCCCGCGGTGCGGGGGGGGC
TGCGAGGGGAACAAAGGCTG
CGTGCGGGGTGTGTGCGTGG
GGGGGTGAGCAGGGGGTGTG
GGCGCGTCGGTCGGGCTGCA
ACCCCCCCTGCACCCCCCTC
CCCGAGTTGCTGAGCACGGC
CCGGCTTCGGGTGCGGGGCT
CCGTACGGGGCGTGGCGCGG
GGCTCGCCGTGCCGGGCGGG
GGGTGGCGGCAGGTGGGGGT
GCCGGGCGGGGCGGGGCCGC
CTCGGGCCGGGGAGGGCTCG
GGGGAGGGGCGCGGCGGCCC
CCGGAGCGCCGGCGGCTGTC
GAGGCGCGGCGAGCCGCAGC
CATTGCCTTTTATGGTAATC
GTGCGAGAGGGCGCAGGGAC
TTCCTTTGTCCCAAATCTGT
GCGGAGCCGAAATCTGGGAG
GCGCCGCCGCACCCCCTCTA
GCGGGCGCGGGGCGAAGCGG
TGCGGCGCCGGCAGGAAGGA
AATGGGCGGGGAGGGCCTTC
GTGCGTCGCCGCGCCGCCGT
CCCCTTCTCCCTCTCCAGCC
TCGGGGCTGTCCGCGGGGGG
ACGGCTGCCTTCGGGGGGGA
CGGGGCAGGGCGGGGTTCGG
CTTCTGGCGTGTGACCGGCG
GCTCTAGAGCCTCTGCTAAC
CATGTTCATGCCTTCTTCTT
TTTCCTACAGCTCCTGGGCA
ACGTGCTGGTTATTGTGCTG
TCTCATCATTTTGGCAAAGA
ATT
PGK 419 GGGGTTGGGGTTGCGCCTTT
TCCAAGGCAGCCCTGGGTTT
GCGCAGGGACGCGGCTGCTC
TGGGCGTGGTTCCGGGAAAC
GCAGCGGCGCCGACCCTGGG
TCTCGCACATTCTTCACGTC
CGTTCGCAGCGTCACCCGGA
TCTTCGCCGCTACCCTTGTG
GGCCCCCCGGCGACGCTTCC
TGCTCCGCCCCTAAGTCGGG
AAGGTTCCTTGCGGTTCGCG
GCGTGCCGGACGTGACAAAC
GGAAGCCGCACGTCTCACTA
GTACCCTCGCAGACGGACAG
CGCCAGGGAGCAATGGCAGC
GCGCCGACCGCGATGGGCTG
TGGCCAATAGCGGCTGCTCA
GCAGGGCGCGCCGAGAGCAG
CGGCCGGGAAGGGGCGGTGC
GGGAGGCGGGGTGTGGGGCG
GTAGTGTGGGCCCTGTTCCT
GCCCGCGCGGTGTTCCGCAT
TCTGCAAGCCTCCGGAGCGC
ACGTCGGCAGTCGGCTCCCT
CGTTGACCGAATCACCGACC
TCTCTCCCCAG
EF-1a 420 GAATTCAGGCTCCGGTGCCC
GTCAGTGGGCAGAGCGCACA
TCGCCCACAGTCCCCGAGAA
GTTGGGGGGAGGGGTCGGCA
ATTGAACCGGTGCCTAGAGA
AGGTGGCGCGGGGTAAACTG
GGAAAGTGATGTCGTGTACT
GGCTCCGCCTTTTTCCCGAG
GGTGGGGGAGAACCGTATAT
AAGTGCAGTAGTCGCCGTGA
ACGTTCTTTTTCGCAACGGG
TTTGCCGCCAGAACACAGGT
AAGTGCCGTGTGTGGTTCCC
GCGGGCCTGGCCTCTTTACG
GGTTATGGCCCTTGCGTGCC
TTGAATTACTTCCACCTGGC
TGCAGTACGTGATTCTTGAT
CCCGAGCTTCGGGTTGGAAG
TGGGTGGGAGAGTTCGAGGC
CTTGCGCTTAAGGAGCCCCT
TCGCCTCGTGCTTGAGTTGA
GGCCTGGCCTGGGCGCTGGG
GCCGCCGCGTGCGAATCTGG
TGGCACCTTCGCGCCTGTCT
CGCTGCTTTCGATAAGTCTC
TAGCCATTTAAAATTTTTGA
TGACCTGCTGCGACGCTTTT
TTTCTGGCAAGATAGTCTTG
TAAATGCGGGCCAAGATCTG
CACACTGGTATTTCGGTTTT
TGGGGCCGCGGGCGGCGACG
GGGCCCGTGCGTCCCAGCGC
ACATGTTCGGCGAGGCGGGG
CCTGCGAGCGCGGCCACCGA
GAATCGGACGGGGGTAGTCT
CAAGCTGGCCGGCCTGCTCT
GGTGCCTGGTCTCGCGCCGC
CGTGTATCGCCCCGCCCTGG
GCGGCAAGGCTGGCCCGGTC
GGCACCAGTTGCGTGAGCGG
AAAGATGGCCGCTTCCCGGC
CCTGCTGCAGGGAGCTCAAA
ATGGAGGACGCGGCGCTCGG
GAGAGCGGGCGGGTGAGTCA
CCCACACAAAGGAAAAGGGC
CTTTCCGTCCTCAGCCGTCG
CTTCATGTGACTCCACGGAG
TACCGGGCGCCGTCCAGGCA
CCTCGATTAGTTCTCGAGCT
TTTGGAGTACGTCGTCTTTA
GGTTGGGGGGAGGGGTTTTA
TGCGATGGAGTTTCCCCACA
CTGAGTGGGTGGAGACTGAA
GTTAGGCCAGCTTGGCACTT
GATGTAATTCTCCTTGGAAT
TTGCCCTTTTTGAGTTTGGA
TCTTGGTTCATTCTCAAGCC
TCAGACAGTGGTTCAAAGTT
TTTTTCTTCCATTTCAGGTG
TCGTGACATCATTTT
Subsequently, keeping the MAD7-RNP amounts constant, the effect of various homology arm lengths (100 vs 500 bp) and HDR template amounts (0.125 μg μL−1, 0.25 μg μL−1, 0.5 μg μL−1, and 1 μg μL−1) on the insertion efficiency was evaluated using JET and EF1a promoters. Up to 30% higher integration efficiency was observed with HDR templates flanked with HA of 500 compared to 100 base pairs. Moreover, the data showed improved insertion efficiencies with increasing amounts of HDR templates flanked with either 100 or 500 base pair HA but at the same time somewhat reduced cell viability (FIG. 19). Specifically, FIG. 19 shows GFP insertion efficiency at AAVS1 (n=3; Mean±SD) in T-cell leukemic cell line measured at days 2, 7, 14, and 21 post-transfection as a function of donor template amount. No transient GFP expression was observed at day 21 post-transfection. Cell viability (black circles) was measured at day 2 post-transfection. Top panels display GFP insertion efficiencies using donor template flanked with short homology arms (100 bp HA), and bottom panels donor template flanked with long homology arms (500 bp HA). Left panels display GFP insertion efficiencies using donor template containing EF-1α promoter (long, ˜2000 bp), and right panels donor template containing JET promoter (short, ˜1000 bp). Amount of donor template, represented by the gradient above the bars, increases from 0.125, 0.25, 0.5 to 1 μg μL−1. Dark grey bars represent mean insertion frequency using crAAVS1. Light grey bars represent mean insertion frequency using crIDTneg (IDT).
Next, using primary T-cells isolated from the human peripheral blood from three donors and a protocol selected from the experiments above, i.e., 150:100 pmol gNA:MAD7 RNP complex together with 1 μg μL−1 HDR template, in combination with 100 μg μL−1 poly-L-glutamic acid (PGA), integration efficiency of a clinically relevant CAR transgene containing JET or EF1a promoter flanked with HA of 100 or 500 base pairs and a bovine growth hormone derived polyadenylation sequence was analyzed. An anti-CD19 CAR with fully human variable regions (Hu19CAR), CD8α hinge and transmembrane domains, a CD28 costimulatory domain, and CD3ζ activation domain was used. Moderate insertion efficiency at AAVS1 but stable CAR expression of up to 14% and 16% was observed using HDR templates flanked with 100 and 500 base pair HA, respectively. The normalized cell viability measured 24 h post-transfection was in same cases relatively low, ranging from 22% with JET-500-CAR, 35% with JET-100-CAR, 43% with EF1a-100-CAR, to 55% with EF1a-500-CAR (FIG. 20). It is important to emphasize, that both CAR insertion efficiency and cell viability were higher in the treatment with PGA compared to the treatment without PGA (P≤0.05; data not shown). Specifically, FIG. 20 shows CAR insertion efficiency at AAVS1 (D=3; n=3; Mean±SD) in primary Pan T-cells measured at days 7 and 11 post-transfection. Cell viability was measured 24 hours post-transfection. Individual panels display CAR insertion efficiencies using donor template structure as described in FIG. 19. Amount of donor template, MAD7-RNP, and PGA was 1 μg μL−1, 100:150 pmol MAD7:gNA, and 100 μg μL−1, in that order. Nucleofection program P3-EH-115 for transfection of primary T-cells was used. D represents number of biological replicas, and n number of technical replicas per D. Dark grey bars represent mean insertion frequency using crAAVS1. Light grey bars represent mean insertion frequency using crIDTneg (IDT).
Multiple parameters were reevaluated to further optimize primary T-cell viability and CAR insertion efficiencies at AAVS1. Using Pan T-cells isolated from the blood from two donors, the effect of RNP amount with 100 μg μL−1 PGA and EF1a-500-CAR template amount on CAR insertion efficiency and cell viability was tested (data not shown). Reducing the RNP amount to 75:50 pmol gNA:MAD7 RNP complex while increasing the donor template amount to 1.5 μg μL−1 led to improved CAR insertion efficiencies without significantly affecting cell viability (P≥0.05; data not shown). In addition, using the abovementioned transfection conditions in combination with the cell recovery in a post-transfection cultivation medium pretreated with 2 μM M3814 resulted in nearly 5-times more efficient CAR insertion than other experiments (FIG. 21). The optimized CRISPR-MAD7 transfection protocol resulted in CAR insertion efficiency of up to 85% 13-days post-transfection (median 65%) together with the median normalized cell viability as high as 62% 24 hours post-transfection. Specifically, FIG. 21 shows CAR insertion efficiency at AAVS1 (D=5; n=3) in primary Pan T-cells measured at day 7 post-transfection, and re-measured in two biological replicas at day 13 post-transfection (D=2; n=3). Cell viability was measured 24 hours post-transfection (D=5; n=3; Mean±SD). Amount or concentration of donor template, MAD7-RNP, PGA, and M3814 was 1.5 μg μL−1, 50:75 pmol MAD7:gNA, 100 μg μL−1, and 2 μM, respectively. Nucleofection program P3-EH-115 for transfection of primary T-cells was used. D represents number of biological replicas, and n number of technical replicas per D. Dark grey bars represent mean insertion frequency using crAAVS1. Light grey bars represent mean insertion frequency using crIDTneg (IDT).
EQUIVALENTS Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and/or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.
The terms “a” and “an” and “the” and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. Where the plural form is used for compounds, salts, or the like, this is taken to mean also a single compound, salt, or the like.
It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.
The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.
Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.
It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present invention remain operable. Moreover, two or more steps or actions may be conducted simultaneously.
The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
Embodiments In embodiment 1 provided herein is a composition comprising a nucleic acid-guided nuclease comprising a Type V CRISPR nuclease polypeptide comprising at least one nuclear localization signal (NLS) at or near the N-terminus or the C-terminus of the polypeptide. In embodiment 2 provided herein is the composition of embodiment 1 wherein the nuclease is a Type Va nuclease. In embodiment 3 provided herein is the composition of embodiment 1 or embodiment 2 wherein the Type V CRISPR nuclease polypeptide has at least 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or 100% sequence identity, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% sequence identity with SEQ ID NO: 1. In embodiment 4 provided herein is the composition of any previous embodiment wherein the Type V CRISPR nuclease polypeptide comprises two NLSs, one or both of which are at or near the N-terminus or the C-terminus of the polypeptide. In embodiment 5 provided herein is the composition of any previous embodiment wherein the Type V CRISPR nuclease polypeptide comprises three NLSs, each of which is at or near the N-terminus or the C-terminus of the polypeptide. In embodiment 6 provided herein is the composition of any previous embodiment wherein the Type V CRISPR nuclease polypeptide comprises four NLSs, each of which is at or near the N-terminus or the C-terminus of the polypeptide. In embodiment 7 provided herein is the composition of any previous embodiment wherein the Type V CRISPR nuclease polypeptide comprises at least five NLSs, each of which is at or near the N-terminus or the C-terminus of the polypeptide. In embodiment 8 provided herein is the composition of any one of embodiments 4 through 7 wherein at least two of the NLSs are at or near the N-terminus of the polypeptide. In embodiment 9 provided herein is the composition of any one of embodiments 5 through 7 wherein at least three of the NLSs are at or near the N-terminus of the polypeptide. In embodiment 10 provided herein is the composition of any one of embodiments 6 through 7 wherein at least four of the NLSs are at or near the N-terminus of the polypeptide. In embodiment 11 provided herein is the composition of embodiment 7 wherein the 5 NLSs are at or near the N-terminus of the polypeptide. In embodiment 12 provided herein is the composition of embodiment 11 comprising a sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to any one of SEQ ID NOs: 109-112. In embodiment 13 provided herein is the composition of any one of embodiments 1 through 3 wherein the Type V CRISPR nuclease polypeptide comprises at least 1-30, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 2-30, 2-20, 2-15, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 3-30, 3-20, 3-15, 3-10, 3-9, 3-8, 3-7, 3-6, or 3-5, preferably 1-10, more preferably 2-10, even more preferably 3-10 NLSs, each of which is at or near the N-terminus or the C-terminus of the polypeptide. In embodiment 14 provided herein is the composition of any one of embodiments 4 through 11 wherein at least two of the NLSs have different nuclear localization mechanisms. In embodiment 15 provided herein is the composition of any one of embodiments 5 through 7 or 9 through 11 wherein at least three of the NLSs have different nuclear localization mechanisms. In embodiment 16 provided herein is the composition of any previous embodiment wherein one or more of the NLSs comprises an NLS of the SV40 virus large T-antigen, an NLS from nucleoplasmin, e.g. a nucleoplasmin bipartite NLS, a c-myc NLS; a hRNPA1 M9 NLS; an IBB domain of importin-alpha NLS; a myoma T protein NLS; a sequence from human p53 NLS; a sequence of mouse c-abl IV NLS; a sequence of influenza virus NS1 NLS; a sequence of Hepatitis virus delta antigen NLS; a sequence of mouse Mx1 protein NLS; a sequence of human poly(ADP-ribose) polymerase NLS; a sequence of steroid hormone receptors (human) glucocorticoid NLS; and/or a sequence of EGL-13 NLS. In embodiment 17 provided herein is the composition of embodiment 16 wherein one or more of the NLSs comprises an NLS of the SV40 virus large T-antigen. In embodiment 18 provided herein is the composition of embodiment 16 wherein two or more of the NLSs comprises an NLS of the SV40 virus large T-antigen. In embodiment 19 provided herein is the composition of embodiment 17 or embodiment 18 wherein the NLS or NLSs comprises the sequence of SEQ ID NO: 5. In embodiment 20 provided herein is the composition of any one of embodiments 16 through 19 wherein one or more of the NLSs comprises an NLS from nucleoplasmin. In embodiment 21 provided herein is the composition of embodiment 20 wherein the nucleoplasmin NLS comprises the sequence of SEQ ID NO: 6. In embodiment 22 provided herein is the composition of any one of embodiments 16 through 21 wherein one or more of the NLSs comprises a c-myc NLS. In embodiment 23 provided herein is the composition of embodiment 22 wherein the c-myc NLS comprises the sequence of SEQ ID NO: 7, SEQ ID NO: 8, or SEQ ID NO: 21. In embodiment 24 provided herein is the composition of embodiment 23 wherein the c-myc NLS comprises the sequence of SEQ ID NO: 21. In embodiment 25 provided herein is the composition of any one of embodiments 16 through 24 wherein one or more of the NLSs comprises a sequence of EGL-13 NLS. In embodiment 26 provided herein is the composition of embodiment 25 wherein the EGL-13 NLS comprises the sequence of SEQ ID NO: 107. In embodiment 27 provided herein is the composition of any previous embodiment wherein the Type V CRISPR nuclease polypeptide further comprises a purification tag. In embodiment 28 provided herein is the composition of embodiment 27 wherein the purification tag is at or near the N-terminus of the nuclease polypeptide. In embodiment 29 provided herein is the composition of embodiment 27 or embodiment 28 wherein the purification tag comprises a poly-his tag, such as a Gly-6×His tag (SEQ ID NO: 421) or Gly-8×His tag (SEQ ID NO: 422); short epitope tags, e.g., FLAG, hemagglutinin (HA), c-myc, T7, Glu-Glu; maltose binding protein (mbp); N-terminal glutathione S-transferase (GST); or calmodulin binding peptide (CBP) In embodiment 30 provided herein is the composition of embodiment 29 wherein the purification tag comprises a poly-his tag. In embodiment 31 provided herein is the composition of embodiment 30 wherein the purification tag comprises a gly-6×His tag (SEQ ID NO: 421). In embodiment 32 provided herein is the composition of embodiment 30 wherein the purification tag comprises a gly-8×His tag (SEQ ID NO: 422). In embodiment 33 provided herein is the composition of any previous embodiment wherein the Type V CRISPR nuclease polypeptide comprises a cleavage site. In embodiment 34 provided herein is the composition of embodiment 33 wherein the cleavage site is at or near the N-terminus of the nuclease polypeptide. In embodiment 35 provided herein is the composition of embodiment 33 or embodiment 34 wherein the cleavage site comprises a Tobacco Etch Virus (TEV) cleavage site. In embodiment 36 provided herein is the composition of embodiment 35 wherein the cleavage site comprises the sequence of SEQ ID NO: 108. In embodiment 37 provided herein is the composition of embodiment 36 comprising 5 NLSs at or near the N-terminus of the polypeptide, a purification tag, and the cleavage site, wherein the cleavage site is after the purification tag. In embodiment 38 provided herein is the composition of embodiment 37 comprising a sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 8%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to SEQ ID NO: 111 or 112. In embodiment 39 provided herein is the composition of embodiment 37 comprising a sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 8%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to SEQ ID NO: 112. In embodiment 40 provided herein is the composition of any previous embodiment further comprising a guide nucleic acid (gNA), e.g., gRNA, comprising a spacer sequence that targets a target nucleotide sequence within a polynucleotide, or a polynucleotide coding for the gNA, e.g., gRNA, wherein the gNA, e.g., gRNA is compatible with the Type V CRISPR nuclease. In embodiment 41 provided herein is the composition of embodiment 40 wherein the target nucleotide is within 50 nucleotides of a protospacer adjacent motif (PAM) sequence specific for the Type V CRISPR nuclease. In embodiment 42 provided herein is the composition of embodiment 41 wherein the PAM comprises a sequence of YTTN, wherein Y is T or C and N is A, T, G, or C. In embodiment 43 provided herein is the composition of embodiment 42 wherein the PAM comprises a sequence of YTTV or TTTV, wherein V is A, G, or C. In embodiment 44 provided herein is the composition of embodiment 40 wherein the gNA is a gRNA. In embodiment 45 provided herein is the composition of embodiment 44 wherein the gRNA is a dual gRNA. In embodiment 46 provided herein is the composition of embodiment 44 or embodiment 45 wherein the composition comprises the gRNA and the gRNA comprises one or more chemical modifications. In embodiment 47 provided herein is the composition of embodiment 46 wherein the chemical modification comprises a 2′-O-alkyl, a 2′-O-methyl, a phosphorothioate, a phosphonoacetate, a thiophosphonoacetate, a 2′-O-methyl-3′-phosphorothioate, a 2′-O-methyl-3′-phosphonoacetate, a 2′-O-methyl-3′-thiophosphonoacetate, a 2′-deoxy-3′-phosphonoacetate, a 2′-deoxy-3′-thiophosphonoacetate, a suitable alternative, or a combination thereof. In embodiment 48 provided herein is the composition of any one of embodiments 44 through 47 wherein a ratio of guanine:uracil in the gRNA is at least 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:42, or 60:40, preferably at least 53:47, more preferably at least 54:46, even more preferably at least 55:45. In embodiment 49 provided herein is the composition of any one of embodiments 40 through 48 wherein the molar ratio of gNA, e.g., gRNA to Type V CRISPR nuclease is at least 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 2:1, 2.2:1, 2.5:1, or 3:1 and/or not more than 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 3:1, or 4:1, preferably 1.1:1 to 2.5:1, more preferably 1.2:1 to 2:1, even more preferably 1.2:1 to 1.7:1. In embodiment 50 provided herein is the composition of any one of embodiments 40 through 49 wherein the molar amount of gNA, e.g., gRNA, is at least 10, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 170, 190 or 200 pmol and/or not more than 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 170, 190, 200, 250, or 300 pmol, preferably 25-200 pmol, more preferably 50-100 pmol, even more preferably 65 to 85 pmol. In embodiment 51 provided herein is the composition of any one of embodiments 40 through 50 further comprising a donor template. In embodiment 52 provided herein is the composition of embodiment 51 wherein the donor template comprises homology arms. In embodiment 53 provided herein is the composition of embodiment 51 or embodiment 52 wherein the donor template is present in an amount of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.7, 2, 2.5, 3, 4, or 5 μg μL−1 and/or not more than 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.7, 2, 2.5, 3, 4, 5, 7, or 10 μg μL−1, preferably 0.3 to 2 μg μL−1, more preferably 0.5 to 1.5 μg μL−1, even more preferably 0.8 to 1.2 μg μL−1. In embodiment 54 provided herein is the composition of any one of embodiments 40 through 53 further comprising an anionic polymer. In embodiment 55 provided herein is the composition of embodiment 54 wherein the anionic polymer comprises polyglutamic acid (PGA). In embodiment 56 provided herein is the composition of embodiment 54 or embodiment 55 wherein the anionic polymer is present at a concentration of at least 20, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 170, 200, 250, 300, 400, or 500 μg μL−1 and/or not more than 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 170, 200, 250, 300, 400, 500, 700, or 1000 μg μL−1, preferably 20 to 200 μg μL−1, more preferably 50 to 150 μg μL−1, even more preferably 80 to 120 μg μL−1.
In embodiment 57 provided herein is a cell containing the composition of any previous embodiment. In embodiment 58 provided herein is the cell of embodiment 56 wherein the cell is a human cell. In embodiment 59 provided herein is the cell of embodiment 58 wherein the cell is an immune cell or a stem cell. In embodiment 60 provided herein is the cell of embodiment 59 wherein the cell is an immune cell. In embodiment 61 provided herein is the cell of embodiment 60 wherein the cell is a T cell. In embodiment 62 provided herein is the cell of embodiment 59 wherein the cell is a stem cell. In embodiment 63 provided herein is the cell of embodiment 62 wherein the cell is an induced pluripotent stem cell (iPSC).
In embodiment 64 provided herein is a method comprising inserting a composition of any one of embodiments 1 through 56 into a cell. In embodiment 65 provided herein is the method of embodiment 64 wherein inserting the composition into the cell comprises electroporation.
In embodiment 66 provided herein is a method for modifying a target polynucleotide comprising (i) contacting the composition of any one of embodiments 40 through 56 and (ii) allowing the nuclease and the guide nucleic acid to modify a targeted genomic region. In embodiment 67 provided herein is the method of embodiment 66 wherein the composition is a composition of any one of embodiments 51 through 56. In embodiment 68 provided herein is the method of embodiment 66 or embodiment 67 wherein the target polynucleotide is a genome or a portion of a genome within a cell. In embodiment 69 provided herein is the method of embodiment 68 wherein the cell is a human cell. In embodiment 70 provided herein is the method of embodiment 69 wherein the cell is an immune cell or a stem cell. In embodiment 71 provided herein is the method of embodiment 70 wherein the cell is an immune cell. In embodiment 72 provided herein is the method of embodiment 71 wherein the cell is a T cell. In embodiment 73 provided herein is the method of embodiment 70 wherein the cell is a stem cell. In embodiment 74 provided herein is the method of embodiment 73 wherein the stem cell is an iPSC In embodiment 75 provided herein is the method of any one of embodiments 67 through 74 wherein the donor template comprises a mutation in a PAM within 50 nucleotides of the target nucleotide sequence in the target polynucleotide. In embodiment 76 provided herein is the method of any one of embodiments 68 through 74 wherein the composition is a composition of embodiment 67 and the donor template comprises a polynucleotide coding for a polypeptide to be expressed by the cell. In embodiment 77 provided herein is the method of embodiment 76 wherein the polypeptide to be expressed by the cell comprises a chimeric antigen receptor (CAR) or a portion thereof. In embodiment 78 provided herein is the method of embodiment 77 wherein the cell is a human T cell or a human iPSC. In embodiment 79 provided herein is the method of embodiment 77 wherein the cell is a human T cell. In embodiment 80 provided herein is the method of embodiment 77 wherein the cell is a human iPSC.
In embodiment 81 provided herein is a composition comprising a first polynucleotide coding for a polypeptide comprising a nucleic acid-guided nuclease comprising a CRISPR Type V nuclease polypeptide, wherein the polynucleotide has less than 75% sequence identity to SEQ ID NO: 22. In embodiment 82 provided herein is the composition of embodiment 81 wherein the nuclease polypeptide comprises at least 1, 2, 3, 4, or 5 NLSs, wherein each of the NLSs is at or near the N-terminus or the C-terminus of the nuclease polypeptide. In embodiment 83 provided herein is the composition of embodiment 82 wherein one or more of the NLSs comprises an NLS of the SV40 virus large T-antigen, an NLS from nucleoplasmin, e.g. a nucleoplasmin bipartite NLS, a c-myc NLS; a hRNPA1 M9 NLS; an IBB domain of importin-alpha NLS; a myoma T protein NLS; a sequence from human p53 NLS; a sequence of mouse c-abl IV NLS; a sequence of influenza virus NS1 NLS; a sequence of Hepatitis virus delta antigen NLS; a sequence of mouse Mx1 protein NLS; a sequence of human poly(ADP-ribose) polymerase NLS; a sequence of steroid hormone receptors (human) glucocorticoid NLS; and/or a sequence of EGL-13 NLS. In embodiment 84 provided herein is the composition of embodiment 83 wherein one or more of the NLSs comprises an NLS of the SV40 virus large T-antigen. In embodiment 85 provided herein is the composition of embodiment 84 wherein the NLS or NLSs comprises the sequence of SEQ ID NO: 5. In embodiment 86 provided herein is the composition of any one of embodiments 83 through 85 wherein one or more of the NLSs comprises an NLS from nucleoplasmin. In embodiment 87 provided herein is the composition of embodiment 86 wherein the nucleoplasmin NLS comprises the sequence of SEQ ID NO: 6. In embodiment 88 provided herein is the composition of any one of embodiments 83 through 87 wherein one or more of the NLSs comprises a c-myc NLS. In embodiment 89 provided herein is the composition of embodiment 88 wherein the c-myc NLS comprises the sequence of SEQ ID NO: 7, SEQ ID NO: 8, or SEQ ID NO: 21. In embodiment 90 provided herein is the composition of embodiment 88 wherein the c-myc NLS comprises the sequence SEQ ID NO: 21. In embodiment 91 provided herein is the composition of any one of embodiments 83 through 90 wherein one or more of the NLSs comprises a sequence of EGL-13 NLS. In embodiment 92 provided herein is the composition of embodiment 91 wherein the EGL-13 NLS comprises the sequence of SEQ ID NO: 107. In embodiment 93 provided herein is the composition of any one of embodiments 82 through 92 wherein the NLS or NLSs is at or near the N-terminus of the polypeptide. In embodiment 94 provided herein is the composition of any one of embodiments 81 through 93 wherein the first polynucleotide comprises a polynucleotide coding for a purification tag. In embodiment 95 provided herein is the composition of embodiment 94 wherein the purification tag is at or near the N-terminus of the nuclease polypeptide. In embodiment 96 provided herein is the composition of embodiment 94 or 95 wherein the purification tag comprises a poly-his tag, such as a Gly-6×His tag (SEQ ID NO: 421) or Gly-8×His tag (SEQ ID NO: 422); short epitope tags, e.g., FLAG, hemagglutinin (HA), c-myc, T7, Glu-Glu; maltose binding protein (mbp); N-terminal glutathione S-transferase (GST); or calmodulin binding peptide (CBP). In embodiment 97 provided herein is the composition of embodiment 96 wherein the purification tag comprises a poly-his tag. In embodiment 98 provided herein is the composition of embodiment 97 wherein the purification tag comprises a gly-6×His tag (SEQ ID NO: 421). In embodiment 99 provided herein is the composition of embodiment 97 wherein the purification tag comprises a gly-8×His tag (SEQ ID NO: 422). In embodiment 100 provided herein is the composition of any one of embodiments 81 through 99 wherein the Type V CRISPR nuclease polypeptide comprises a cleavage site. In embodiment 101 provided herein is the composition of embodiment 100 wherein the cleavage site is at or near the N-terminus of the nuclease polypeptide. In embodiment 102 provided herein is the composition of embodiment 100 or 101 wherein the cleavage site comprises a Tobacco Etch Virus (TEV) cleavage site. In embodiment 103 provided herein is the composition of embodiment 102 wherein the cleavage site comprises the sequence of SEQ ID NO: 108. In embodiment 104 provided herein is the composition of embodiment 103 comprising 5 NLSs at or near the N-terminus of the polypeptide, a purification tag, and the cleavage site, wherein the cleavage site is after the purification tag. In embodiment 105 provided herein is the composition of any one of embodiments 81 through 104 wherein the polynucleotide codes for a polypeptide comprising a sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to any one of SEQ ID NOs: 109-112 In embodiment 106 provided herein is the composition of any one of embodiments 81 through 105 wherein the polynucleotide codes for a polypeptide comprising a sequence at least 60, 70, 80, 85, 90, 95, 98, 99%, or 100%, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical identical to SEQ ID NO: 112. In embodiment 107 provided herein is the composition of any one of embodiments 81 through 105 wherein the first polynucleotide comprises a sequence at least 50, 60, 70, 80, 90, 95, 97, or 99% identical, or 100% identical, preferably at least 80%, more preferably at least 90%, even more preferably at least 95%, still more preferably at least 98% identical to SEQ ID NO: 113. In embodiment 108 provided herein is the composition of any one of embodiments 81 through 107 further comprising a second polynucleotide coding for a gNA or portion thereof, wherein the gNA, e.g., gRNA, comprises a spacer sequence that targets a target nucleotide sequence within a polynucleotide, or a polynucleotide coding for the gNA, e.g., gRNA, wherein the gNA, e.g., gRNA is compatible with the Type V CRISPR nuclease. In embodiment 109 provided herein is the composition of embodiment 108 wherein the first and second polynucleotides are the same. In embodiment 110 provided herein is the composition of any one of embodiments 81 through 109 further comprising third polynucleotide that comprises a donor template.
In embodiment 111 provided herein is a vector comprising the polynucleotide or polynucleotides of any one of embodiments 81 through 110.
In embodiment 112 provided herein is a cell comprising a composition of any one of embodiments 81 through 110. In embodiment 113 provided herein is the composition of embodiment 112 wherein the cell is a human cell. In embodiment 114 provided herein is the composition of embodiment 113 wherein the cell is an immune cell or a stem cell. In embodiment 115 provided herein is the composition of embodiment 113 wherein the cell is an immune cell. In embodiment 116 provided herein is the composition of embodiment 115 wherein the cell is T cell. In embodiment 117 provided herein is the composition of embodiment 113 wherein the cell is a stem cell. In embodiment 118 provided herein is the composition of embodiment 117 wherein the cell is an iPSC.
In embodiment 119 provided herein is a method comprising inserting the composition of any one of embodiments 81 through 111 into a cell. In embodiment 120 provided herein is the method of embodiment 119 wherein inserting the composition into the cell comprises electroporation.
In embodiment 121 provided herein is a method comprising (i) inserting a composition of any one of embodiments 81 through 107 into a cell and (ii) inserting a gNA, e.g. a gRNA, compatible with the Type V CRISPR nuclease coded for by the composition, into the cell. In embodiment 122 provided herein is the method of embodiment 121 wherein steps (i) and (ii) comprise electroporation.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
