ADENOVIRUS POLYNUCLEOTIDES AND POLYPEPTIDES

There is provided inter alia an isolated polynucleotide, wherein the polynucleotide encodes a polypeptide selected from the group consisting of: (a) a polypeptide having the amino acid sequence according to SEQ ID NO: 1, (b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1, and (c) a polypeptide having the amino acid sequence according to SEQ ID NO: 3.

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Description
CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of copending U.S. application Ser. No. 15/735,872 filed Dec. 12, 2017, which is the National Phase under 35 U.S.C. § 371 of International Application No. PCT/EP2016/063297, filed on Jun. 10, 2016, which claims the benefit under 35 U.S.C. § 119(a) to Patent Application No. PCT/EP2015/063248, filed in European Patent Office on Jun. 12, 2015, Patent Application No. 1514772.1, filed in United Kingdom on Aug. 19, 2015, and Patent Application No. 1510357.5, filed in United Kingdom on Jun. 12, 2015, all of which are hereby expressly incorporated by reference into the present application.

FIELD OF THE INVENTION

The present invention relates to isolated polynucleotide and polypeptide sequences derived from novel chimp adenovirus ChAd155, as well as to recombinant polynucleotides, vectors, adenoviruses and compositions comprising said polynucleotide and polypeptide sequences.

BACKGROUND OF THE INVENTION

Adenovirus has been widely used for gene transfer applications due to its ability to achieve highly efficient gene transfer in a variety of target tissues and large transgene capacity. Conventionally, E1 genes of adenovirus are deleted and replaced with a transgene cassette consisting of the promoter of choice, cDNA sequence of the gene of interest and a poly A signal, resulting in a replication defective recombinant virus.

Recombinant adenoviruses are useful in gene therapy and as vaccines. Viral vectors based on chimpanzee adenovirus represent an alternative to the use of human derived Ad vectors for the development of genetic vaccines. Adenoviruses isolated from chimpanzees are closely related to adenoviruses isolated from humans as demonstrated by their efficient propagation in cells of human origin. However, since human and chimp adenoviruses are close relatives, serologic cross reactivity between the two virus species is possible.

There is a demand for vectors which effectively deliver molecules to a target and minimize the effect of pre-existing immunity to selected adenovirus serotypes in the population. One aspect of pre-existing immunity that is observed in humans is humoral immunity, which can result in the production and persistence of antibodies that are specific for adenoviral proteins. The humoral response elicited by adenovirus is mainly directed against the three major structural capsid proteins: fiber, penton and hexon.

Vectors, compositions and methods of the present invention may have one or more following improved characteristics over the prior art, including but not limited to higher productivity, improved immunogenicity and increased transgene expression. Vectors of the present invention may find use in the expression of one or more immunogens useful to immunise a human or non-human animal against a pathogen.

Respiratory syncytial virus (RSV) is a highly contagious human pathogen that causes respiratory tract infections in people of all ages. During the first year of life, 50-70% of infants are infected with RSV and essentially all children have had an RSV infection by their second birthday. The risk for severe RSV-associated lower respiratory tract infections (LRTI) is highest in infants below 6 months of age and is a leading cause for hospitalization. Infection with RSV does not confer full protective immunity. Symptomatic RSV re-infections are common later in life and continue throughout adulthood. These re-infections generally go undiagnosed because they usually present as common acute upper respiratory tract infections. In more vulnerable persons (e.g., immunocompromised adults or elderly), re-infections can however also lead to severe disease.

To date, no vaccine is available against RSV and treatment of RSV disease is largely symptomatic and supportive care. The antiviral drug ribavirin is currently the only approved antiviral therapy for RSV treatment, but its use is restricted to severe hospitalized cases due to uncertainties regarding its efficacy, difficulty in administration (aerosol) and high cost [American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis, 2006]. RSV-specific monoclonal antibodies (palivizumab, Synagis™, Medimmune) are indicated for the prevention of serious LRTIs requiring hospitalization caused by RSV in children at high risk for RSV disease but are not indicated or recommended in the general, healthy infant population due to high cost and the need for repeated administration.

In the late 1960s, a formalin-inactivated whole virus RSV vaccine (FI-RSV) tested in clinical trials led to more severe clinical symptoms upon subsequent natural infection with RSV in children under the age of two [Kim, 1969; Chin, 1969]). This experience has led to heightened safety concerns with pediatric RSV vaccine candidates. Since that time, several investigational vaccines have been and continue to be explored, including live attenuated viral vaccines and those based upon purified or recombinant viral proteins. However there is not yet a licensed vaccine for the prevention of RSV disease.

SUMMARY OF THE INVENTION

There is provided an isolated polynucleotide, wherein the polynucleotide encodes a polypeptide selected from the group consisting of:

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1, and

(c) a polypeptide having the amino acid sequence according to SEQ ID NO: 3.

Also provided is a recombinant polynucleotide comprising a polynucleotide selected from the group consisting of:

(a) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(b) a polynucleotide which encodes a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1, and

(c) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 3.

Also provided is a recombinant vector comprising a polynucleotide selected from the group consisting of:

(a) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(b) a polynucleotide which encodes a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1, and

(c) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 3.

Also provided is a recombinant adenovirus comprising at least one polynucleotide or polypeptide selected from the group consisting of:

(a) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(b) a polynucleotide which encodes a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1,

(c) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 3,

(d) a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(e) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1, and

(f) a polypeptide having the amino acid sequence according to SEQ ID NO: 3.

Also provided is a composition comprising at least one of the following:

(a) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(b) a polynucleotide which encodes a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1,

(c) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 3,

(d) a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(e) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1,

(f) a polypeptide having the amino acid sequence according to SEQ ID NO: 3,

(g) a vector comprising a polynucleotide as described in (a), (b) or (c) above, and

(h) a recombinant adenovirus comprising a polynucleotide as described in (a), (b) or (c) above, and a pharmaceutically acceptable excipient.

Also provided is a cell comprising at least one of the following:

(a) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(b) a polynucleotide which encodes a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1,

(c) a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 3,

(d) a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(e) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1,

(f) a polypeptide having the amino acid sequence according to SEQ ID NO: 3,

(g) a vector comprising a polynucleotide as described in (a), (b) or (c) above, and

(h) a recombinant adenovirus comprising a polynucleotide as described in (a), (b) or (c) above.

Also provided is an isolated adenoviral polypeptide selected from the group consisting of:

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 1,

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1, and

(c) a polypeptide having the amino acid sequence according to SEQ ID NO: 3.

Also provided is an isolated polynucleotide, vector, recombinant adenovirus, composition or cell comprising or consisting of the sequence according to SEQ ID NO: 6.

DESCRIPTION OF THE FIGURES

FIG. 1A-C—Alignment of fiber protein sequences from the indicated simian adenoviruses.

    • ChAd3 (SEQ ID NO:27)
    • PanAd3 (SEQ ID NO:28)
    • ChAd17 (SEQ ID NO:29)
    • ChAd19 (SEQ ID NO:30)
    • ChAd24 (SEQ ID NO:31)
    • ChAd155 (SEQ ID NO:1)
    • ChAd11 (SEQ ID NO:32)
    • ChAd20 (SEQ ID NO:33)
    • ChAd31 (SEQ ID NO:34)
    • PanAd1 (SEQ ID NO:35)
    • PanAd2 (SEQ ID NO:36)

FIG. 2—Flow diagram for production of specific ChAd155 BAC and plasmid vectors

FIG. 3—Species C BAC Shuttle #1365 schematic

FIG. 4—pArsChAd155 Ad5E4orf6-2 (#1490) schematic

FIG. 5—pChAd155/RSV schematic

FIG. 6—BAC ChAd155/RSV schematic

FIG. 7—Productivty of ChAd3 and ChAd155 vectors expressing an HIV Gag transgene (Experiment 1)

FIG. 8—Productivity of ChAd3 and ChAd155 vectors expressing an HIV Gag transgene (Experiment 2)

FIG. 9—Productivity of PanAd3 and ChAd155 vectors expressing RSV transgene

FIG. 10—Expression levels of ChAd3 and ChAd155 vectors expressing an HIV Gag transgene

FIG. 11—Expression levels of PanAd3 and ChAd155 vectors expressing an HIV Gag transgene—Western Blot

FIG. 12—Immunogenicity of ChAd3 and ChAd155 vectors expressing an HIV Gag transgene—IFN-gamma ELISpot

FIG. 13—Immunogenicity of PanAd3 and ChAd155 vectors expressing an HIV Gag transgene—IFN-gamma ELISpot

FIG. 14—Schematic of the synthetic DNA fragment used to express RSV antigens by the ChAd155-RSV vector

FIG. 15—Anti-F antibody titers induced by ChAd155-RSV and PanAd3-RSV in BALB/c mice

FIG. 16—RSV titers in nasal tissues (A) and lung homogenates (B), RSV neutralizing antibody (C) and pathology score (D) after viral challenge

FIG. 17—Kinetics of induction of bRSV-specific IgG (A) and RSV neutralizing antibodies (B)

FIG. 18—Kinetics of mean virus titers in nasopharyngeal swabs detected up to day 6 post bRSV challenge

FIG. 19—Effect of vaccination on bRSV replication in the lower respiratory tract

FIG. 20—Effect of vaccination on gross pneumonic consolidation 6 days post bRSV challenge

FIG. 21—Effect of vaccination on the pulmonary inflammatory response 6 days post bRSV challenge

 DESCRIPTION OF THE SEQUENCES

    • SEQ ID NO: 1—Polypeptide sequence of ChAd155 fiber
    • SEQ ID NO: 2—Polynucleotide sequence encoding ChAd155 fiber
    • SEQ ID NO: 3—Polypeptide sequence of ChAd155 penton
    • SEQ ID NO: 4—Polynucleotide sequence encoding ChAd155 penton
    • SEQ ID NO: 5—Polypeptide sequence of ChAd155 hexon
    • SEQ ID NO: 6—Polynucleotide sequence encoding ChAd155 hexon
    • SEQ ID NO: 7—Polynucleotide sequence encoding ChAd155#1434
    • SEQ ID NO: 8—Polynucleotide sequence encoding ChAd155#1390
    • SEQ ID NO: 9—Polynucleotide sequence encoding ChAd155#1375
    • SEQ ID NO: 10—Polynucleotide sequence encoding wild type ChAd155
    • SEQ ID NO: 11—Polynucleotide sequence encoding ChAd155/RSV
    • SEQ ID NO: 12—Polynucleotide sequence encoding the CASI promoter
    • SEQ ID NO: 13—Ad5orf6 primer 1 polynucleotide sequence
    • SEQ ID NO: 14—Ad5orf6 primer 2 polynucleotide sequence
    • SEQ ID NO: 15—BAC/CHAd155 ΔE1_TetO hCMV RpsL-Kana primer 1 polynucleotide sequence
    • SEQ ID NO: 16—BAC/CHAd155 ΔE1_TetO hCMV RpsL-Kana (#1375) primer 2 polynucleotide sequence
    • SEQ ID NO: 17—1021-FW E4 Del Step1 primer polynucleotide sequence
    • SEQ ID NO: 18—1022-RW E4 Del Step1 primer polynucleotide sequence
    • SEQ ID NO: 19—1025-FW E4 Del Step2 primer polynucleotide sequence
    • SEQ ID NO: 20—1026-RW E4 Del Step2 primer polynucleotide sequence
    • SEQ ID NO: 21—91-SubMonte FW primer polynucleotide sequence
    • SEQ ID NO: 22—890-BghPolyA RW primer polynucleotide sequence
    • SEQ ID NO: 23—CMVfor primer polynucleotide sequence
    • SEQ ID NO: 24—CMVrev primer polynucleotide sequence
    • SEQ ID NO: 25—CMVFAM-TAMRA qPCR probe polynucleotide sequence
    • SEQ ID NO: 26—Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) polynucleotide sequence
    • SEQ ID NO: 27—Amino acid sequence for the fiber protein of ChAd3
    • SEQ ID NO: 28—Amino acid sequence for the fiber protein of PanAd3
    • SEQ ID NO: 29—Amino acid sequence for the fiber protein of ChAd17
    • SEQ ID NO: 30—Amino acid sequence for the fiber protein of ChAd19
    • SEQ ID NO: 31—Amino acid sequence for the fiber protein of ChAd24
    • SEQ ID NO: 32—Amino acid sequence for the fiber protein of ChAd11
    • SEQ ID NO: 33—Amino acid sequence for the fiber protein of ChAd20
    • SEQ ID NO: 34—Amino acid sequence for the fiber protein of ChAd31
    • SEQ ID NO: 35—Amino acid sequence for the fiber protein of PanAd1

SEQ ID NO: 36—Amino acid sequence for the fiber protein of PanAd2

SEQ ID NO: 37—RSV FΔTM-N-M2-1 amino acid sequence

    • SEQ ID NO: 38—HIV Gag polynucleotide sequence

DETAILED DESCRIPTION OF THE INVENTION

Adenovirus

Adenoviruses have a characteristic morphology with an icosahedral capsid comprising three major proteins, hexon (II), penton base (III) and a knobbed fiber (IV), along with a number of other minor proteins, VI, VIII, IX, IIIa and IVa2. The virus genome is a linear, double-stranded DNA. The virus DNA is intimately associated with the highly basic protein VII and a small peptide pX (formerly termed mu). Another protein, V, is packaged with this DNA-protein complex and provides a structural link to the capsid via protein VI. The virus also contains a virus-encoded protease, which is necessary for processing of some of the structural proteins to produce mature infectious virus.

The adenoviral genome is well characterized. There is general conservation in the overall organization of the adenoviral genome with respect to specific open reading frames being similarly positioned, e.g. the location of the E1A, E1B, E2A, E2B, E3, E4, L1, L2, L3, L4 and L5 genes of each virus. Each extremity of the adenoviral genome comprises a sequence known as an inverted terminal repeat (ITR), which is necessary for viral replication. The virus also comprises a virus-encoded protease, which is necessary for processing some of the structural proteins required to produce infectious virions. The structure of the adenoviral genome is described on the basis of the order in which the viral genes are expressed following host cell transduction. More specifically, the viral genes are referred to as early (E) or late (L) genes according to whether transcription occurs prior to or after onset of DNA replication. In the early phase of transduction, the E1A, E1B, E2A, E2B, E3 and E4 genes of adenovirus are expressed to prepare the host cell for viral replication. During the late phase of infection, expression of the late genes L1-L5, which encode the structural components of the virus particles, is activated.

Adenoviruses are species-specific and different serotypes, i.e., types of viruses that are not cross-neutralized by antibodies, have been isolated from a variety of mammalian species. For example, more than 50 serotypes have been isolated from humans which are divided into six subgroups (A-F; B is subdivided into B1 and B2) based on sequence homology and on their ability to agglutinate red blood cells (Tatsis and Ertl Molecular Therapy (2004) 10:616-629). Numerous adenoviruses have been isolated from nonhuman simians such as chimpanzees, bonobos, rhesus macaques and gorillas, and they are classified into the same human groups based on phylogenetic relationships based on hexon or fiber sequences (Colloca et al. (2012) Science Translational Medicine 4:1-9; Roy et al. (2004) Virology 324: 361-372; Roy et al. (2010) Journal of Gene Medicine 13:17-25).

Adenovirus Capsid Proteins including the Fiber Protein and Polynucleotides Encoding these Proteins

As outlined above, the adenoviral capsid comprises three major proteins, hexon, penton and fiber. The hexon accounts for the majority of the structural components of the capsid, which consists of 240 trimeric hexon capsomeres and 12 penton bases. The hexon has three conserved double barrels, while the top has three towers, each tower containing a loop from each subunit that forms most of the capsid. The base of hexon is highly conserved between adenoviral serotypes, while the surface loops are variable (Tatsis and Ertl Molecular Therapy (2004) 10:616-629).

Penton is another adenoviral capsid protein that forms a pentameric base to which fiber attaches. The trimeric fiber protein protrudes from the penton base at each of the 12 vertices of the capsid and is a knobbed rod-like structure. A remarkable difference in the surface of adenovirus capsids compared to that of most other icosahedral viruses is the presence of the long, thin fiber protein. The primary role of the fiber protein is the tethering of the viral capsid to the cell surface via its interaction with a cellular receptor.

The fiber proteins of many adenovirus serotypes share a common architecture: an N-terminal tail, a central shaft made of repeating sequences, and a C-terminal globular knob domain (or “head”). The central shaft domain consists of a variable number of beta-repeats. The beta-repeats connect to form an elongated structure of three intertwined spiralling strands that is highly rigid and stable. The shaft connects the N-terminal tail with the globular knob structure, which is responsible for interaction with the target cellular receptor. The globular nature of the adenovirus knob domain presents large surfaces for binding the receptor laterally and apically. The effect of this architecture is to project the receptor-binding site far from the virus capsid, thus freeing the virus from steric constraints presented by the relatively flat capsid surface.

Although fibers of many adenovirus serotypes have the same overall architecture, they have variable amino acid sequences that influence their function as well as structure. For example, a number of exposed regions on the surface of the fiber knob present an easily adaptable receptor binding site. The globular shape of the fiber knob allows receptors to bind at the sides of the knob or on top of the fiber knob. These binding sites typically lie on surface-exposed loops connecting beta-strands that are poorly conserved among human adenoviruses. The exposed side chains on these loops give the knob a variety of surface features while preserving the tertiary and quaternary structure. For example, the electrostatic potential and charge distributions at the knob surfaces can vary due to the wide range of isoelectric points in the fiber knob sequences, from pl approximately 9 for Ad 8, Ad 19, and Ad 37 to approximately 5 for subgroup B adenoviruses. As a structurally complex virus ligand, the fiber protein allows the presentation of a variety of binding surfaces (knob) in a number of orientations and distances (shaft) from the viral capsid.

One of the most obvious variations between some serotypes is fiber length. Studies have shown that the length of the fiber shaft strongly influences the interaction of the knob and the virus with its target receptors. Further, fiber proteins between serotypes can also vary in their ability to bend. Although beta-repeats in the shaft form a highly stable and regular structure, electron microscopy (EM) studies have shown distinct hinges in the fiber. Analysis of the protein sequence from several adenovirus serotype fibers pinpoints a disruption in the repeating sequences of the shaft at the third beta-repeat from the N-terminal tail, which correlates strongly with one of the hinges in the shaft, as seen by EM. The hinges in the fiber allow the knob to adopt a variety of orientations relative to the virus capsid, which may circumvent steric hindrances to receptor engagement requiring the correct presentation of the receptor binding site on the knob. For example, the rigid fibers of subgroup D Ads thus require a flexible receptor or one prepositioned for virus attachment, as they are unable to bend themselves. (Nicklin et al Molecular Therapy 2005 12:384-393)

The identification of specific cell receptors for different Ad serotypes and the knowledge of how they contribute to tissue tropism have been achieved through the use of fiber pseudotyping technology. Although Ads of some subgroups use CAR as a primary receptor, it is becoming clear that many Ads use alternate primary receptors, leading to vastly different tropism in vitro and in vivo. The fibers of these serotypes show clear differences in their primary and tertiary structures, such as fiber shaft rigidity, the length of the fiber shaft, and the lack of a CAR binding site and/or the putative HSPG binding motif, together with the differences in net charge within the fiber knob. Pseudotyping Ad 5 particles with an alternate fiber shaft and knob therefore provides an opportunity to remove important cell binding domains and, in addition, may allow more efficient (and potentially more cell-selective) transgene delivery to defined cell types compared to that achieved with Ad 5. Neutralization of fiber-pseudotyped Ad particles may also be reduced if the fibers used are from Ads with lower seroprevalence in humans or experimental models, a situation that favours successful administration of the vector (Nicklin et al Molecular Therapy (2005) 12:384-393). Furthermore, full length fiber as well as isolated fiber knob regions, but not hexon or penton alone, are capable of inducing dendritic cell maturation and are associated with induction of a potent CD8+ T cell response (Molinier-Frenkel et al. J. Biol. Chem. (2003) 278:37175-37182). Taken together, adenoviral fiber plays an important role in at least receptor-binding and immunogenicity of adenoviral vectors.

Illustrating the differences between the fiber proteins of Group C simian adenoviruses is the alignment provided in FIG. 1. A striking feature is that the fiber sequences of these adenoviruses can be broadly grouped into having a long fiber, such as ChAd155, or a short fiber, such as ChAd3. This length differential is due to a 36 amino acid deletion at approximately position 321 in the short fiber relative to the long fiber. In addition, there are a number of amino acid substitutions that differ between the short versus long fiber subgroup yet are consistent within each subgroup. While the exact function of these differences have not yet been elucidated, given the function and immunogenicity of fiber, they are likely to be significant. It has been shown that one of the determinants of viral tropism is the length of the fiber shaft. It has been demonstrated that an Ad5 vector with a shorter shaft has a lower efficiency of binding to CAR receptor and a lower infectivity (Ambriović-Ristov A. et al.: Virology. (2003) 312(2):425-33): It has been speculated that this impairment is the results of an increased rigidity of the shorter fiber leading to a less efficient attachment to the cell receptor (Wu, E et al.: J Virol. (2003) 77(13): 7225-7235). These studies may explain the improved properties of ChAd155 carrying a longer and more flexible fiber in comparison with the previously described ChAd3 and PanAd3 carrying a fiber with a shorter shaft.

In one aspect of the invention there is provided isolated fiber, penton and hexon capsid polypeptides of chimp adenovirus ChAd155 and isolated polynucleotides encoding the fiber, penton and hexon capsid polypeptides of chimp adenovirus ChAd155.

All three capsid proteins are expected to contribute to low seroprevalence and can, thus, be used independently from each other or in combination to suppress the affinity of an adenovirus to preexisting neutralizing antibodies, e.g. to manufacture a recombinant adenovirus with a reduced seroprevalence. Such a recombinant adenovirus may be a chimeric adenovirus with capsid proteins from different serotypes with at least a fiber protein from ChAd155.

The ChAd155 fiber polypeptide sequence is provided in SEQ ID NO: 1.

The ChAd155 penton polypeptide sequence is provided in SEQ ID NO: 3.

The ChAd155 hexon polypeptide sequence is provided in SEQ ID NO: 5.

Polypeptides, Recombinant Adenoviruses, Compositions or Cells comprising Polypeptide Sequences of ChAd155 Fiber or a Functional Derivative thereof

Suitably the isolated polypeptide, recombinant adenovirus, composition or cell of the invention comprises a polypeptide having the amino acid sequence according to SEQ ID NO: 1.

Suitably the polypeptide, recombinant adenovirus, composition or cell of the invention comprises a polypeptide which is a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1. Suitably the functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1 has an amino acid sequence which is at least 80% identical, such as at least 85.0% identical, such as at least 90% identical, such as at least 91.0% identical, such as at least 93.0% identical, such as at least 95.0% identical, such as at least 97.0% identical, such as at least 98.0% identical, such as at least 99.0% identical, such as at least 99.2% identical, such as at least 99.4% identical, such as 99.5% identical, such as at least 99.6% identical, such as at least 99.8% identical, such as 99.9% identical over its entire length to the amino acid sequence of SEQ ID NO: 1. Alternatively the functional derivative has no more than 130, more suitably no more than 120, more suitably no more than 110, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 1.

Suitably the polypeptide, recombinant adenovirus, composition or cell according to the invention further comprises:

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 3; or

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 3, wherein the functional derivative has an amino acid sequence which is at least 50.0% identical over its entire length to the amino acid sequence of SEQ ID NO: 3, and/or

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 5; or

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 5, wherein the functional derivative has an amino acid sequence which is at least 50% identical over its entire length to the amino acid sequence of SEQ ID NO: 5.

Suitably the functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 3 has an amino acid sequence which is at least 60.0%, such as at least 70.0%, such as at least 80.0%, such as at least 85.0%, such as at least 90.0%, such as at least 91.0% identical, such as at least 93.0% identical, such as at least 95.0% identical, such as at least 97.0% identical, such as at least 98.0% identical, such as at least 99.0%, such as at least 99.2%, such as at least 99.4%, such as 99.5% identical, such as at least 99.6%, such as 99.7% identical such as at least 99.8% identical, such as 99.9% identical over its entire length to the amino acid sequence of SEQ ID NO: 3. Alternatively the functional derivative has no more than 300, more suitably no more than 250, more suitably no more than 200, more suitably no more than 150, more suitably no more than 125, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 3.

Suitably the functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 5 has an amino acid sequence which is at least 60.0%, such as at least 70.0%, such as at least 80.0%, such as at least 85.0%, such as at least 90.0%, such as at least 91.0% identical, such as at least 93.0% identical, such as at least 95.0% identical, such as at least 97.0% identical, such as at least 98.0% identical, such as at least 99.0%, such as at least 99.2%, such as at least 99.4%, such as 99.5% identical, such as at least 99.6%, such as 99.7% identical such as at least 99.8% identical, such as 99.9% identical over its entire length to the amino acid sequence of SEQ ID NO: 5. Alternatively the functional derivative has no more than 500, more suitably no more than 400, more suitably no more than 450, more suitably no more than 300, more suitably no more than 250, more suitably no more than 200, more suitably no more than 150, more suitably no more than 125, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 5.

Polypeptides, Recombinant Adenoviruses, Compositions or Cells comprising Polypeptide Sequences of ChAd155 Penton

Suitably the polypeptide, recombinant adenovirus, composition or cell of the invention comprises a polypeptide having the amino acid sequence according to SEQ ID NO: 3.

Suitably the polypeptide, recombinant adenovirus, composition or cell of the invention further comprises:

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 1; or

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1 and/or

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 5; or

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 5, wherein the functional derivative has an amino acid sequence which is at least 60% identical over its entire length to the amino acid sequence of SEQ ID NO: 5.

Suitably the functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1 has an amino acid sequence which is at least 60.0% identical, such as at least 70.0% identical, such as at least 80.0% identical, such as at least 85.0% identical, such as at least 87.0% identical, such as at least 89.0% identical, such as at least 91.0% identical, such as at least 93.0% identical, such as at least 95.0% identical, such as at least 97.0% identical, such as at least 98.0% identical, such as at least 99.0% identical, such as at least 99.2%, such as at least 99.4%, such as 99.5% identical, such as at least 99.6%, such as at least 99.8% identical, such as 99.9% identical over its entire length to the amino acid sequence of SEQ ID NO: 1. Alternatively the functional derivative has no more than 130, more suitably no more than 120, more suitably no more than 110, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 1.

Suitably the functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 5 has an amino acid sequence which is at least 60.0%, such as at least 70.0%, such as at least 80.0%, such as at least 85.0%, such as at least 90.0%, such as at least 95.0%, such as at least 97.0%, such as at least 99.0%, such as at least 99.0%, such as at least 99.2%, such as at least 99.4%, such as 99.5% identical, such as at least 99.6%, such as at least 99.8% identical, such as 99.9% identical over its entire length to the amino acid sequence of SEQ ID NO:5. Alternatively the functional derivative has no more than 500, more suitably no more than 400, more suitably no more than 450, more suitably no more than 300, more suitably no more than 250, more suitably no more than 200, more suitably no more than 150, more suitably no more than 125, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 5.

Isolated Polynucleotides, Vectors, Recombinant Adenoviruses, Compositions or Cells comprising Polynucleotides Encoding ChAd155 Fiber or a Functional Derivative thereof

Suitably the isolated polynucleotide, vector, recombinant adenovirus, thereof composition or cell of the invention comprises a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 1. Suitably the polynucleotide has a sequence according to SEQ ID NO: 2.

Alternatively, the polynucleotide, vector, recombinant adenovirus, composition or cell of the invention comprises a polynucleotide which encodes a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence of SEQ ID NO: 1. Suitably the functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1 has an amino acid sequence which is at least 80% identical, such as at least 85.0% identical, such as at least 90% identical, such as at least 91.0% identical, such as at least 93.0% identical, such as at least 95.0% identical, such as at least 97.0% identical, such as at least 98.0% identical, such as at least 99.0% identical, such as at least 99% identical, such as at least 99.4% identical, such as at least 99.6% identical, such as at least 99.8% identical over its entire length to the amino acid sequence of SEQ ID NO: 1. Alternatively the functional derivative has no more than 130, more suitably no more than 120, more suitably no more than 110, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 1.

Suitably the polynucleotide, vector, recombinant adenovirus, composition or cell of the invention further comprises a polynucleotide encoding:

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 3; or

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 3, wherein the functional derivative has an amino acid sequence which is at least 50.0% identical over its entire length to the amino acid sequence of SEQ ID NO: 3, and/or

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 5; or

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 5, wherein the functional derivative has an amino acid sequence which is at least 50% identical over its entire length to the amino acid sequence of SEQ ID NO: 5.

Suitably the functional derivative of the polypeptide having the amino acid sequence according to SEQ ID NO: 3 has an amino acid sequence which is at least 60.0%, such as at least 70.0%, such as at least 80.0%, such as at least 85.0%, such as at least 90.0%, such as at least 91.0% identical, such as at least 93.0% identical, such as at least 95.0% identical, such as at least 97.0% identical, such as at least 98.0% identical, such as at least 99.0%, such as at least 99%, such as at least 99.4%, such as at least 99.6%, such as at least 99.8% identical over its entire length to the amino acid sequence of SEQ ID NO: 3. Alternatively the functional derivative has no more than 300, more suitably no more than 250, more suitably no more than 200, more suitably no more than 150, more suitably no more than 125, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 3.

Suitably the functional derivative of the polypeptide having the amino acid sequence according to SEQ ID NO: 5 has an amino acid sequence which is at least 60.0%, such as at least 70.0%, such as at least 80.0%, such as at least 85.0%, such as at least 90.0%, such as at least 95.0%, such as at least 97.0%, such as at least 98.0%, such as at least 99.0%, such as at least 99.2%, such as at least 99.4%, such as 99.5% identical, such as at least 99.6%, such as 99.7% identical such as at least 99.8% identical, such as 99.9% identical over its entire length to the amino acid sequence of SEQ ID NO: 5. Alternatively the functional derivative has no more than 500, more suitably no more than 400, more suitably no more than 450, more suitably no more than 300, more suitably no more than 250, more suitably no more than 200, more suitably no more than 150, more suitably no more than 125, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 5.

Isolated Polynucleotides, Vectors, Recombinant Adenoviruses, Compositions or Cells comprising Polynucleotides Encoding ChAd155 Penton

Suitably the isolated polynucleotide, vector, recombinant adenovirus, composition or cell of the invention comprises a polynucleotide which encodes a polypeptide having the amino acid sequence according to SEQ ID NO: 3. Suitably the polynucleotide has a sequence according to SEQ ID NO: 4.

Suitably the polynucleotide, vector, recombinant adenovirus, composition or cell of the invention further comprises a polynucleotide encoding:

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 1; or

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1, wherein the functional derivative has an amino acid sequence which is at least 50% identical over its entire length to the amino acid sequence of SEQ ID NO: 1 and/or

(a) a polypeptide having the amino acid sequence according to SEQ ID NO: 5; or

(b) a functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 5, wherein the functional derivative has an amino acid sequence which is at least 50% identical over its entire length to the amino acid sequence of SEQ ID NO: 5.

Suitably the functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 1 has an amino acid sequence which is at least 60.0% identical, such as at least 70.0% identical, such as at least 80.0% identical, such as at least 85.0% identical, such as at least 87.0% identical, such as at least 89.0% identical, such as at least 91.0% identical, such as at least 93.0% identical, such as at least 95.0% identical, such as at least 97.0% identical, such as at least 98.0% identical, such as at least 99.0%, such as at least 99.2%, such as at least 99.4%, such as 99.5% identical, such as at least 99.6%, such as 99.7% identical such as at least 99.8% identical, such as 99.9% identical over its entire length to the amino acid sequence of SEQ ID NO: 1. Alternatively the functional derivative has no more than 130, more suitably no more than 120, more suitably no more than 110, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 1.

Suitably the functional derivative of a polypeptide having the amino acid sequence according to SEQ ID NO: 5 has an amino acid sequence which is at least 60.0%, such as at least 70.0%, such as at least 80.0%, such as at least 85.0%, such as at least 90.0%, such as at least 95.0%, such as at least 97.0%, such as at least 98.0%, such as at least 99.0%, such as at least 99.2%, such as at least 99.4%, such as 99.5% identical, such as at least 99.6%, such as 99.7% identical such as at least 99.8% identical, such as 99.9% identical over its entire length to the amino acid sequence of SEQ ID NO: 5. Alternatively the functional derivative has no more than 500, more suitably no more than 400, more suitably no more than 450, more suitably no more than 300, more suitably no more than 250, more suitably no more than 200, more suitably no more than 150, more suitably no more than 125, more suitably no more than 100, more suitably no more than 90, more suitably no more than 80, more suitably no more than 70, more suitably no more than 60, more suitably no more than 50, more suitably no more than 40, more suitably no more than 30, more suitably no more than 20, more suitably no more than 10, more suitably no more than 5, more suitably no more than 4, more suitably no more than 3, more suitably no more than 2, more suitably no more than 1 addition(s), deletion(s) or substitutions(s) compared to SEQ ID NO: 5.

ChAd155 Backbones

The invention provides isolated polynucleotide sequences of chimp adenovirus ChAd155, including that of wild type, unmodified ChAd155 (SEQ ID NO: 10) and modified backbone constructs of ChAd155. These modified backbone constructs include ChAd155#1434 (SEQ ID NO: 7), ChAd155#1390 (SEQ ID NO: 8) and ChAd155#1375 (SEQ ID NO: 9). ChAd155 backbones may be used in the construction of recombinant replication-competent or replication-incompetent adenoviruses for example for the delivery of transgenes.

Annotation of the ChAd155 wild type sequence (SEQ ID NO: 10) sequence is provided below.

LOCUS ChAd155 37830 bp DNA linear 10-JUN-2015 DEFINITION Chimp adenovirus 155, complete genome. COMMENT Annotation according to alignment of ChAd155 against  the human Adenovirus 2 reference strain NC_001405 Two putative ORFs in the E3 region added manually FEATURES Location/Qualifiers source 1 . . . 37830 /organism = “Chimpanzee adenovirus 155” /mol_type =  “genomic DNA” /acronym = “ChAd155” repeat_region 1 . . . 101 /standard_name = “ITR” /rpt_type = inverted gene 466 . . . 1622 /gene = “E1A” TATA_signal 466 . . . 471 /gene = “E1A” prim_transcript 497 . . . 1622 /gene = “E1A” CDS join(577 . . . 1117, 1231 . . . 1532) /gene = “E1A” /product = “E1A_280R” CDS join(577 . . . 979, 1231 . . . 1532) /gene = “E1A” /product = “E1A_243R” polyA_signal 1600 . . . 1605 /gene = “E1A” gene 1662 . . . 4131 /gene = “E1B” TATA_signal 1662 . . . 1667 /gene = “E1B” prim_transcript 1692 . . . 4131 /gene = “E1B” CDS 1704 . . . 2267 /gene = “E1B” /product = “E1B_19K” CDS 2009 . . . 3532 /gene = “E1B” /product = “E1B_55K” gene 3571 . . . 4131 /gene = “IX” TATA_signal 3571 . . . 3576 /gene = “IX” prim_transcript 3601 . . . 4131 /gene = “IX” CDS 3628 . . . 4092 /gene = “IX” /product = “IX” polyA_signal 4097 . . . 4102 /note = “E1B, IX” gene complement(4117 . . . 27523) /gene = “E2B” prim_transcript complement(4117 . . . 27494) /gene = “E2B” gene complement(4117 . . . 5896) /gene = “IVa2” prim_transcript complement(4117 . . . 5896) /gene = “IVa2” CDS complement(join(4151 . . . 5487, 5766 . . . 5778)) /gene = “IVa2” /product = “E2B_IVa2” polyA_signal complement(4150 . . . 4155) /note = “IVa2, E2B” CDS complement(join(5257 . . . 8838, 14209 . . . 14217)) /gene = “E2B” /product = “E2B_polymerase” gene 6078 . . . 34605 /gene = “L5” gene 6078 . . . 28612 /gene = “L4” gene 6078 . . . 22658 /gene = “L3” gene 6078 . . . 18164 /gene = “L2” gene 6078 . . . 14216 /gene = “L1” TATA_signal 6078 . . . 6083 /note = “L” prim_transcript 6109 . . . 34605 /gene = “L5” prim_transcript 6109 . . . 28612 /gene = “L4” prim_transcript 6109 . . . 22658 /gene = “L3” prim_transcript 6109 . . . 18164 /gene = “L2” prim_transcript 6109 . . . 14216 /gene = “L1” CDS join(8038 . . . 8457, 9722 . . . 9742) /gene = “L1” /product = “L1_13.6K” CDS complement(join(8637 . . . 10640, 14209 . . . 14217)) /gene = “E2B” /product = “E2B_pTP” gene 10671 . . . 10832 /gene = “VAI” misc_RNA 10671 . . . 10832 /gene = “VAI” /product = “VAI” gene 10902 . . . 11072 /gene = “VAII” misc_RNA 10902 . . . 11072 /gene = “VAII” /product = “VAII” CDS 11093 . . . 12352 /gene = “L1” /product = “L1_52K” CDS 12376 . . . 14157 /gene = “L1” /product = “L1_pIIIa” polyA_signal 14197 . . . 14202 /gene = “L1” CDS 14254 . . . 16035 /gene = “L2” /product = “L2_penton” CDS 16050 . . . 16646 /gene = “L2” /product = “L2_pVII” CDS 16719 . . . 17834 /gene = “L2” /product = “L2_V” CDS 17859 . . . 18104 /gene = “L2” /product = “L2_pX” polyA_signal 18143 . . . 18148 /gene = “L2” CDS 18196 . . . 18951 /gene = “L3” /product = “L3_pVI” CDS 19063 . . . 21945 /gene = “L3” /product = “L3_hexon” CDS 21975 . . . 22604 /gene = “L3” /product = “L3_protease” polyA_signal 22630 . . . 22635 /gene = “L3” gene complement(22632 . . . 27523) /gene = “E2A” prim_transcript complement(22632 . . . 27494) /gene = “E2A” gene complement(22632 . . . 26357) /gene = “E2A-L” prim_transcript complement(22632 . . . 26328) /gene = “E2A-L” polyA_signal complement(22649 . . . 22654) /note = “E2A, E2A-L” CDS complement(22715 . . . 24367) /gene = “E2A” /note = “DBP; genus-common; DBP family” /codon_start = 1 /product = “E2A” CDS 24405 . . . 26915 /gene = “L4” /product = “L4_100k” TATA_signal complement(26352 . . . 26357) /gene = “E2A-L” CDS join(26602 . . . 26941, 27147 . . . 27529) /gene = “L4” /product = “L4_33K” CDS 26602 . . . 27207 /gene = “L4” /product = “L4_22K” TATA_signal complement(27518 . . . 27523) /note = “E2A, E2B; nominal” CDS 27604 . . . 28287 /gene = “L4” /product = “L4_pVIII” gene 27969 . . . 32686 /gene = “E3B” gene 27969 . . . 31611 /gene = “E3A” TATA_signal 27969 . . . 27974 /note = “E3A, E3B” prim_transcript 27998 . . . 32686 /gene = “E3B” prim_transcript 27998 . . . 31611 /gene = “E3A” CDS 28288 . . . 28605 /gene = “E3A” /product = “E3 ORF1” polyA_signal 28594 . . . 28599 /gene = “L4” CDS 29103 . . . 29303 /gene = “E3A” /product = “E3 ORF2” CDS 29300 . . . 29797 /gene = “E3A” /product = “E3 ORF3” CDS 29826 . . . 30731 /gene = “E3A” /product = “E3 ORF4” CDS 30728 . . . 31579 /gene = “E3A” /product = “E3 ORF5” CDS 31283 . . . 31579 /gene = “E3A” /product = “E3 ORF6” polyA_signal 31578 . . . 31584 /gene = “E3A” CDS 31591 . . . 31863 /gene = “E3B” /product = “E3 ORF7” CDS 31866 . . . 32264 /gene = “E3B” /product = “E3 ORF8” CDS 32257 . . . 32643 /gene = “E3B” /product = “E3 ORF9” polyA_signal 32659 . . . 32664 /gene = “E3B” gene complement(<32678 . . . 32838) /gene = “U” CDS complement(<32678 . . . 32838) /gene = “U” /note = “exon encoding C terminus unidentified; genus-common” /product = “protein U” CDS 32849 . . . 34585 /gene = “L5” /product = “L5_fiber” polyA_signal 34581 . . . 34586 /gene = “L5” gene complement(34611 . . . 37520) /gene = “E4” prim_transcript complement(34611 . . . 37490) /gene = “E4” polyA_signal complement(34625 . . . 34630) /gene = “E4” CDS complement(join)34794 . . . 35069, 35781 . . . 35954)) /gene = “E4” /product = “E4 0RF7” CDS complement(35070 . . . 35954) /gene = “E4” /product = “E4 ORF6” CDS complement(35875 . . . 36219) /gene = “E4” /product = “E4 ORF4” CDS complement(36235 . . . 36582) /gene = “E4” /product = “E4 ORF3” CDS complement(36579 . . . 36971) /gene = “E4” /product = “E4 ORF2” CDS complement(37029 . . . 37415) /gene = “E4” /product = “E4 ORF1” TATA_signal complement(37515 . . . 37520) /gene = “E4” repeat_region 37740 . . . 37830 /standard_name = “ITR” /rpt_type = inverted

In one embodiment, fragments of the sequences of SEQ ID NO: 7, 8, 9, 10 and their complementary strands, cDNA and RNA complementary thereto are provided. Suitably, fragments are at least 15 nucleotides in length, more suitably 30 nucleotides in length, more suitably 60 nucleotides in length, more suitably 120 nucleotides in length, more suitably 240, more suitably 480 nucleotides in length and encompass functional fragments, i.e., fragments which are of biological interest. For example, a functional fragment can express a desired adenoviral product or may be useful in production of recombinant viral vectors. Such fragments include the gene sequences listed above.

Gene products of the ChAd155 adenovirus, such as proteins, enzymes, and fragments thereof, which are encoded by the adenoviral nucleic acids described herein are provided. Such proteins include those encoded by the open reading frames identified above and the proteins encoded by the polynucleotides provided in the Sequence Listing.

Further ChAd155 Polynucleotides and Polypeptides

In some embodiments the polynucleotide of the invention comprises a polynucleotide encoding a fiber polypeptide; a penton polypeptide; a hexon polypeptide and penton polypeptide; a hexon polypeptide and fiber polypeptide; penton polypeptide and fiber polypeptide; or hexon polypeptide, penton polypeptide and fiber polypeptide of the invention; and may further comprise additional adenoviral polynucleotides, suitably ChAd155 polynucleotides. Thus, suitably the polynucleotide according to the invention comprises one or more of the following, the sequence coordinates relative to SEQ ID NO:10 provided in the previous annotation:

    • (a) an adenoviral 5′-inverted terminal repeat (ITR);
    • (b) an adenoviral E1A region, or a fragment thereof selected from among the E1A_280R and E1A_243R regions;
    • (c) an adenoviral E1B or IX region, or a fragment thereof selected from among the group consisting of the E1B_19K, E1B_55K and IX regions;
    • (d) an adenoviral E2B region; or a fragment thereof selected from among the group consisting of the E2B_pTP, E2B_polymerase and E2B_IVa2 regions;
    • (e) an adenoviral L1 region, or a fragment thereof, said fragment encoding an adenoviral protein selected from the group consisting of the L1_13.6K, L1_52K and L1_pIIIa protein;
    • (f) an adenoviral L2 region or a L2 region comprising a polynucleotide encoding the penton protein of the invention, or a fragment thereof, said fragment encoding an adenoviral protein selected from the group consisting of the L2_penton protein, the L2_pVII protein, the L2_V protein and the L2_pX protein;
    • (g) an adenoviral L3 region or a L3 region comprising a polynucleotide encoding the hexon protein of the invention, or a fragment thereof, said fragment encoding an adenoviral protein selected from the group consisting of the L3_pVI protein, the L3_hexon protein and the L3_protease protein;
    • (h) an adenoviral E2A region;
    • (i) an adenoviral L4 region, or a fragment thereof said fragment encoding an adenoviral protein selected from the group consisting of the L4_100k protein, the L4_33K protein, the L4_22K protein and protein L4_VIII;
    • (j) an adenoviral E3 region, or a fragment thereof selected from the group consisting of E3 ORF1, E3 ORF2, E3 ORF3, E3 ORF4, E3 ORF5, E3 ORF6, E3 ORF7, E3 ORF8, and E3 ORF9;
    • (k) an adenoviral L5 region or a L5 region comprising a polynucleotide encoding the L5_fiber fiber polypeptide of the invention
    • (l) an adenoviral (such as Ad5) E4 region, or a fragment thereof selected from the group consisting of E4 ORF7, E4 ORF6, E4 ORF4, E4 ORF3, E4 ORF2, and E4 ORF1; in particular ORF6 of said E4 region;
    • (m) an adenoviral 3′-ITR; and/or
    • (n) an adenoviral VAI or VAII RNA region, preferably an adenoviral VAI or VAII RNA region from an adenovirus other than ChAd155, more preferably from Ad5.

Definitions

Suitably the polynucleotides or polypeptides of the invention are isolated. An “isolated” polynucleotide is one that is removed from its original environment. For example, a naturally-occurring polynucleotide is isolated if it is separated from some or all of the coexisting materials in the natural system. A polynucleotide is considered to be isolated if, for example, it is cloned into a vector that is not a part of its natural environment or if it is comprised within cDNA.

Suitably the polynucleotides of the invention are recombinant. Recombinant means that the polynucleotide is the product of at least one of cloning, restriction or ligation steps, or other procedures that result in a polynucleotide that is distinct from a polynucleotide found in nature. A recombinant adenovirus is an adenovirus comprising a recombinant polynucleotide. A recombinant vector is a vector comprising a recombinant polynucleotide. ‘A recombinant virus’ includes progeny of the original recombinant virus. ‘A recombinant vector’ includes replicates of the original recombinant vector. ‘A recombinant polynucleotide’ includes replicates of the original recombinant polynucleotide.

Suitably, the polypeptide sequence of the present invention contains at least one alteration with respect to a native sequence. Suitably, the polynucleotide sequences of the present invention contain at least one alteration with respect to a native sequence. For example, a polynucleotide introduced by genetic engineering techniques into a plasmid or vector derived from a different species (and often a different genus, subfamily or family) is a heterologous polynucleotide. A promoter removed from its native coding sequence and operatively linked to a coding sequence with which it is not naturally found linked is a heterologous promoter. A specific recombination site that has been cloned into a genome of a virus or viral vector, wherein the genome of the virus does not naturally contain it, is a heterologous recombination site. A heterologous nucleic acid sequence also includes a sequence naturally found in an adenoviral genome, but located at a non-native position within the adenoviral vector.

Typically, “heterologous” means derived from a genotypically distinct entity from that of the rest of the entity to which it is being compared. A heterologous nucleic acid sequence refers to any nucleic acid sequence that is not isolated from, derived from, or based upon a naturally occurring nucleic acid sequence of the adenoviral vector. “Naturally occurring” means a sequence found in nature and not synthetically prepared or modified. A sequence is “derived” from a source when it is isolated from a source but modified (e.g., by deletion, substitution (mutation), insertion, or other modification), suitably so as not to disrupt the normal function of the source gene.

A “functional derivative” of a polypeptide suitably refers to a modified version of a polypeptide, e.g. wherein one or more amino acids of the polypeptide may be deleted, inserted, modified and/or substituted. A derivative of an unmodified adenoviral capsid protein is considered functional if, for example:

    • (a) an adenovirus comprising the derivative capsid protein within its capsid retains substantially the same or a lower seroprevalence compared to an adenovirus comprising the unmodified capsid protein and/or
    • (b) an adenovirus comprising the derivative capsid protein within its capsid retains substantially the same or a higher host cell infectivity compared to an adenovirus comprising the unmodified capsid protein and/or
    • (c) an adenovirus comprising the derivative capsid protein within its capsid retains substantially the same or a higher immunogenicity compared to an adenovirus comprising the unmodified capsid protein and or
    • (d) an adenovirus comprising the derivative capsid protein within its capsid retains substantially the same or a higher level of transgene productivity compared to an adenovirus comprising the unmodified capsid protein.

Properties (a)-(d) above may suitably be measured using the methods described in the Examples section below.

Suitably, the polypeptide, vector or recombinant adenovirus has a low seroprevalence in a human population. “Low seroprevalence” may mean having a reduced pre-existing neutralizing antibody level as compared to human adenovirus 5 (Ad5). Similarly or alternatively, “low seroprevalence” may mean less than about 20% seroprevalence, less than about 15% seroprevalence, less than about 10% seroprevalence, less than about 5% seroprevalence, less than about 4% seroprevalence, less than about 3% seroprevalence, less than about 2% seroprevalence, less than about 1% seroprevalence or no detectable seroprevalence. Seroprevalence can be measured as the percentage of individuals having a clinically relevant neutralizing titre (defined as a 50% neutralisation titer >200) using methods as described in Aste-Amézaga et al., Hum. Gene Ther. (2004) 15(3):293-304.

The terms polypeptide, peptide and protein are used interchangeably herein.

The term “simian” is typically meant to encompass nonhuman primates, for example Old World monkeys, New World monkeys, apes and gibbons. In particular, simian may refer to nonhuman apes such as chimpanzees (Pan troglodyte), bonobos (Pan paniscus) and gorillas (genus Gorilla). Non-ape simians may include rhesus macaques (Macaca mulatta)

Sequence Comparison

For the purposes of comparing two closely-related polynucleotide or polypeptide sequences, the “% identity” between a first sequence and a second sequence may be calculated using an alignment program, such as BLAST® (available at blast.ncbi.nlm.nih.gov, last accessed 9 Mar. 2015) using standard settings. The % identity is the number of identical residues divided by the number of residues in the reference sequence, multiplied by 100. The identity figures referred to above and in the claims are percentages calculated by this methodology. An alternative definition of % identity is the number of identical residues divided by the number of aligned residues, multiplied by 100. Alternative methods include using a gapped method in which gaps in the alignment, for example deletions in one sequence relative to the other sequence, are accounted for in a gap score or a gap cost in the scoring parameter. For more information, see the BLAST® fact sheet available at ftp.ncbi.nlm.nih.gov/pub/factsheets/HowTo_BLASTGuide.pdf, last accessed on 9 Mar. 2015.

Sequences that preserve the functionality of the polynucleotide or a polypeptide encoded thereby are likely to be more closely identical. Polypeptide or polynucleotide sequences are said to be the same as or identical to other polypeptide or polynucleotide sequences, if they share 100% sequence identity over their entire length.

A “difference” between sequences refers to an insertion, deletion or substitution of a single amino acid residue in a position of the second sequence, compared to the first sequence. Two polypeptide sequences can contain one, two or more such amino acid differences. Insertions, deletions or substitutions in a second sequence which is otherwise identical (100% sequence identity) to a first sequence result in reduced percent sequence identity. For example, if the identical sequences are 9 amino acid residues long, one substitution in the second sequence results in a sequence identity of 88.9%. If the identical sequences are 17 amino acid residues long, two substitutions in the second sequence results in a sequence identity of 88.2%. If the identical sequences are 7 amino acid residues long, three substitutions in the second sequence results in a sequence identity of 57.1%. If first and second polypeptide sequences are 9 amino acid residues long and share 6 identical residues, the first and second polypeptide sequences share greater than 66% identity (the first and second polypeptide sequences share 66.7% identity). If first and second polypeptide sequences are 17 amino acid residues long and share 16 identical residues, the first and second polypeptide sequences share greater than 94% identity (the first and second polypeptide sequences share 94.1% identity). If first and second polypeptide sequences are 7 amino acid residues long and share 3 identical residues, the first and second polypeptide sequences share greater than 42% identity (the first and second polypeptide sequences share 42.9% identity).

Alternatively, for the purposes of comparing a first, reference polypeptide sequence to a second, comparison polypeptide sequence, the number of additions, substitutions and/or deletions made to the first sequence to produce the second sequence may be ascertained. An addition is the addition of one amino acid residue into the sequence of the first polypeptide (including addition at either terminus of the first polypeptide). A substitution is the substitution of one amino acid residue in the sequence of the first polypeptide with one different amino acid residue. A deletion is the deletion of one amino acid residue from the sequence of the first polypeptide (including deletion at either terminus of the first polypeptide).

For the purposes of comparing a first, reference polynucleotide sequence to a second, comparison polynucleotide sequence, the number of additions, substitutions and/or deletions made to the first sequence to produce the second sequence may be ascertained. An addition is the addition of one nucleotide residue into the sequence of the first polynucleotide (including addition at either terminus of the first polynucleotide). A substitution is the substitution of one nucleotide residue in the sequence of the first polynucleotide with one different nucleotide residue. A deletion is the deletion of one nucleotide residue from the sequence of the first polynucleotide (including deletion at either terminus of the first polynucleotide).

Suitably substitutions in the sequences of the present invention may be conservative substitutions. A conservative substitution comprises the substitution of an amino acid with another amino acid having a chemical property similar to the amino acid that is substituted (see, for example, Stryer et al, Biochemistry, 5th Edition 2002, pages 44-49). Preferably, the conservative substitution is a substitution selected from the group consisting of: (i) a substitution of a basic amino acid with another, different basic amino acid; (ii) a substitution of an acidic amino acid with another, different acidic amino acid; (iii) a substitution of an aromatic amino acid with another, different aromatic amino acid; (iv) a substitution of a non-polar, aliphatic amino acid with another, different non-polar, aliphatic amino acid; and (v) a substitution of a polar, uncharged amino acid with another, different polar, uncharged amino acid. A basic amino acid is preferably selected from the group consisting of arginine, histidine, and lysine. An acidic amino acid is preferably aspartate or glutamate. An aromatic amino acid is preferably selected from the group consisting of phenylalanine, tyrosine and tryptophane. A non-polar, aliphatic amino acid is preferably selected from the group consisting of glycine, alanine, valine, leucine, methionine and isoleucine. A polar, uncharged amino acid is preferably selected from the group consisting of serine, threonine, cysteine, proline, asparagine and glutamine. In contrast to a conservative amino acid substitution, a non-conservative amino acid substitution is the exchange of one amino acid with any amino acid that does not fall under the above-outlined conservative substitutions (i) through (v).

Vectors and Recombinant Adenovirus

The ChAd155 sequences of the invention are useful as therapeutic agents and in construction of a variety of vector systems, recombinant adenovirus and host cells. Suitably the term “vector” refers to a nucleic acid that has been substantially altered (e.g., a gene or functional region that has been deleted and/or inactivated) relative to a wild type sequence and/or incorporates a heterologous sequence, i.e.,nucleic acid obtained from a different source (also called an “insert”), and replicating and/or expressing the inserted polynucleotide sequence, when introduced into a cell (e.g., a host cell). For example, the insert may be all or part of the ChAd155 sequences described herein. In addition or alternatively, a ChAd155 vector may be a ChAd155 adenovirus comprising one or more deletions or inactivations of viral genes, such as E1 or other viral gene or functional region described herein. Such a ChAd155, which may or may not comprise a heterologous sequence, is often called a “backbone” and may be used as is or as a starting point for additional modifications to the vector.

A vector may be any suitable nucleic acid molecule including naked DNA, a plasmid, a virus, a cosmid, phage vector such as lambda vector, an artificial chromosome such as a BAC (bacterial artificial chromosome), or an episome. Alternatively, a vector may be a transcription and/or expression unit for cell-free in vitro transcription or expression, such as a T7-compatible system. The vectors may be used alone or in combination with other adenoviral sequences or fragments, or in combination with elements from non-adenoviral sequences. The ChAd155 sequences are also useful in antisense delivery vectors, gene therapy vectors, or vaccine vectors. Thus, further provided are gene delivery vectors, and host cells which contain the ChAd155 sequences.

The term “replication-competent” adenovirus refers to an adenovirus which can replicate in a host cell in the absence of any recombinant helper proteins comprised in the cell. Suitably, a “replication-competent” adenovirus comprises the following intact or functional essential early genes: E1A, E1B, E2A, E2B, E3 and E4. Wild type adenoviruses isolated from a particular animal will be replication competent in that animal.

The term “replication-incompetent” or “replication-defective” adenovirus refers to an adenovirus which is incapable of replication because it has been engineered to comprise at least a functional deletion (or “loss-of-function” mutation), i.e. a deletion or mutation which impairs the function of a gene without removing it entirely, e.g. introduction of artificial stop codons, deletion or mutation of active sites or interaction domains, mutation or deletion of a regulatory sequence of a gene etc, or a complete removal of a gene encoding a gene product that is essential for viral replication, such as one or more of the adenoviral genes selected from E1A, E1B, E2A, E2B, E3 and E4 (such as E3 ORF1, E3 ORF2, E3 ORF3, E3 ORF4, E3 ORF5, E3 ORF6, E3 ORF7, E3 ORF8, E3 ORF9, E4 ORF7, E4 ORF6, E4 ORF4, E4 ORF3, E4 ORF2 and/or E4 ORF1). Particularly suitably E1 and optionally E3 and/or E4 are deleted. If deleted, the aforementioned deleted gene region will suitably not be considered in the alignment when determining % identity with respect to another sequence.

The present invention provides vectors such as recombinant adenovirus that deliver a protein, suitably a heterologous protein, to cells, either for therapeutic or vaccine purposes. A vector may include any genetic element including naked DNA, a phage, transposon, cosmid, episome, plasmid, or a virus. Such vectors contain DNA of ChAd155 as disclosed herein and a minigene. By “minigene” (or “expression cassette”) is meant the combination of a selected heterologous gene (transgene) and the other regulatory elements necessary to drive translation, transcription and/or expression of the gene product in a host cell.

Typically, a ChAd155-derived adenoviral vector is designed such that the minigene is located in a nucleic acid molecule which contains other adenoviral sequences in the region native to a selected adenoviral gene. The minigene may be inserted into an existing gene region to disrupt the function of that region, if desired. Alternatively, the minigene may be inserted into the site of a partially or fully deleted adenoviral gene. For example, the minigene may be located in the site of a mutation, insertion or deletion which renders non-functional at least one gene of a genomic region selected from the group consisting of E1A, E1B, E2A, E2B, E3 and E4. The term “renders non-functional” means that a sufficient amount of the gene region is removed or otherwise disrupted, so that the gene region is no longer capable of producing functional products of gene expression. If desired, the entire gene region may be removed (and suitably replaced with the minigene).

For example, for a production vector useful for generation of a recombinant virus, the vector may contain the minigene and either the 5′ end of the adenoviral genome or the 3′ end of the adenoviral genome, or both the 5′ and 3′ ends of the adenoviral genome. The 5′ end of the adenoviral genome contains the 5′ cis-elements necessary for packaging and replication; i.e., the 5′ ITR sequences (which function as origins of replication) and the native 5′ packaging enhancer domains (that contain sequences necessary for packaging linear Ad genomes and enhancer elements for the E1 promoter). The 3′ end of the adenoviral genome includes the 3′ cis-elements (including the ITRs) necessary for packaging and encapsidation. Suitably, a recombinant adenovirus contains both 5′ and 3′ adenoviral cis-elements and the minigene (suitably containing a transgene) is located between the 5′ and 3′ adenoviral sequences. A ChAd155-based adenoviral vector may also contain additional adenoviral sequences.

Suitably, ChAd155-based vectors contain one or more adenoviral elements derived from the adenoviral ChAd155 genome of the invention. In one embodiment, the vectors contain adenoviral ITRs from ChAd155 and additional adenoviral sequences from the same adenoviral serotype. In another embodiment, the vectors contain adenoviral sequences that are derived from a different adenoviral serotype than that which provides the ITRs.

As defined herein, a pseudotyped adenovirus refers to an adenovirus in which the capsid proteins of the adenovirus are from a different adenovirus than the adenovirus which provides the ITRs.

Further, chimeric or hybrid adenoviruses may be constructed using the adenoviruses described herein using techniques known to those of skill in the art (e.g., U.S. Pat. No. 7,291,498).

ITRs and any other adenoviral sequences present in the vector of the present invention may be obtained from many sources. A variety of adenovirus strains are available from the American Type Culture Collection, Manassas, Va., or available by request from a variety of commercial and institutional sources. Further, the sequences of many such strains are available from a variety of databases including, e.g., PubMed and GenBank. Homologous adenovirus vectors prepared from other chimp or from human adenoviruses are described in the published literature (for example, U.S. Pat. No. 5,240,846). The DNA sequences of a number of adenovirus types are available from GenBank, including type Ad5 (GenBank Accession Number M73370). The adenovirus sequences may be obtained from any known adenovirus serotype, such as serotypes 2, 3, 4, 7, 12 and 40, and further including any of the presently identified human types. Similarly adenoviruses known to infect nonhuman animals (e.g., simians) may also be employed in the vector constructs of this invention (e.g., U.S. Pat. No. 6,083,716). The viral sequences, helper viruses (if needed), and recombinant viral particles, and other vector components and sequences employed in the construction of the vectors described herein may be obtained as described below.

Sequence, Vector and Adenovirus Production

The sequences of the invention may be produced by any suitable means, including recombinant production, chemical synthesis, or other synthetic means. Suitable production techniques are well known to those of skill in the art. Alternatively, peptides can also be synthesized by well known solid phase peptide synthesis methods.

The adenoviral plasmids (or other vectors) may be used to produce adenoviral vectors. In one embodiment, the adenoviral vectors are adenoviral particles which are replication-incompetent. In one embodiment, the adenoviral particles are rendered replication-incompetent by deletions in the E1A and/or E1B genes. Alternatively, the adenoviruses are rendered replication-incompetent by another means, optionally while retaining the E1A and/or E1B genes. Similarly, in some embodiments, reduction of an immune response to the vector may be accomplished by deletions in the E2B and/or DNA polymerase genes. The adenoviral vectors can also contain other mutations to the adenoviral genome, e.g., temperature-sensitive mutations or deletions in other genes. In other embodiments, it is desirable to retain an intact E1A and/or E1B region in the adenoviral vectors. Such an intact E1 region may be located in its native location in the adenoviral genome or placed in the site of a deletion in the native adenoviral genome (e.g., in the E3 region).

In the construction of adenovirus vectors for delivery of a gene to a mammalian (such as human) cell, a range of modified adenovirus nucleic acid sequences can be employed in the vectors. For example, all or a portion of the adenovirus delayed early gene E3 may be eliminated from the adenovirus sequence which forms a part of the recombinant virus. The function of E3 is believed to be irrelevant to the function and production of the recombinant virus particle. Adenovirus vectors may also be constructed having a deletion of at least the ORF6 region of the E4 gene, and more desirably because of the redundancy in the function of this region, the entire E4 region. Still another vector of the invention contains a deletion in the delayed early gene E2A. Deletions may also be made in any of the late genes L1 to L5 of the adenovirus genome. Similarly, deletions in the intermediate genes IX and IVa2 may be useful for some purposes. Other deletions may be made in the other structural or non-structural adenovirus genes. The above discussed deletions may be used individually, i.e., an adenovirus sequence for use as described herein may contain deletions in only a single region. Alternatively, deletions of entire genes or portions thereof effective to destroy their biological activity may be used in any combination. For example, in one exemplary vector, the adenovirus sequence may have deletions of the E1 genes and the E4 gene, or of the E1, E2A and E3 genes, or of the E1 and E3 genes, or of E1, E2A and E4 genes, with or without deletion of E3, and so on. Any one or more of the E genes may suitably be replaced with an E gene (or one or more E gene open reading frames) sourced from a different strain of adenovirus. Particularly suitably the ChAd155 E1 and E3 genes are deleted and the ChAd155E4 gene is replaced with E4Ad5orf6. As discussed above, such deletions and/or substitutions may be used in combination with other mutations, such as temperature-sensitive mutations, to achieve a desired result.

An adenoviral vector lacking one or more essential adenoviral sequences (e.g., E1A, E1B, E2A, E2B, E4 ORF6, L1, L2, L3, L4 and L5) may be cultured in the presence of the missing adenoviral gene products which are required for viral infectivity and propagation of an adenoviral particle. These helper functions may be provided by culturing the adenoviral vector in the presence of one or more helper constructs (e.g., a plasmid or virus) or a packaging host cell.

Complementation of Replication-Incompetent Vectors

To generate recombinant adenoviruses deleted in any of the genes described above, the function of the deleted gene region, if essential to the replication and infectivity of the virus, must be supplied to the recombinant virus by a helper virus or cell line, i.e., a complementation or packaging cell line.

Helper Viruses

Depending upon the adenovirus gene content of the viral vectors employed to carry the minigene, a helper adenovirus or non-replicating virus fragment may be used to provide sufficient adenovirus gene sequences necessary to produce an infective recombinant viral particle containing the minigene. Useful helper viruses contain selected adenovirus gene sequences not present in the adenovirus vector construct and/or not expressed by the packaging cell line in which the vector is transfected. In one embodiment, the helper virus is replication-defective and contains adenovirus genes in addition, suitably, to one or more of the sequences described herein. Such a helper virus is suitably used in combination with an E1 expressing (and optionally additionally E3 expressing) cell line.

A helper virus may optionally contain a reporter gene. A number of such reporter genes are known to the art as well as described herein. The presence of a reporter gene on the helper virus which is different from the transgene on the adenovirus vector allows both the adenoviral vector and the helper virus to be independently monitored. This reporter is used to enable separation between the resulting recombinant virus and the helper virus upon purification.

Complementation Cell Lines

In many circumstances, a cell line expressing the one or more missing genes which are essential to the replication and infectivity of the virus, such as human E1, can be used to transcomplement a chimp adenoviral vector. This is particularly advantageous because, due to the diversity between the chimp adenovirus sequences of the invention and the human adenovirus sequences found in currently available packaging cells, the use of the current human E1-containing cells prevents the generation of replication-competent adenoviruses during the replication and production process.

Alternatively, if desired, one may utilize the sequences provided herein to generate a packaging cell or cell line that expresses, at a minimum, the E1 gene from ChAd155 under the transcriptional control of a promoter for expression in a selected parent cell line. Inducible or constitutive promoters may be employed for this purpose. Examples of such promoters are described in detail elsewhere in this document. A parent cell is selected for the generation of a novel cell line expressing any desired ChAd155 gene. Without limitation, such a parent cell line may be HeLa [ATCC Accession No. CCL 2], A549 [ATCC Accession No. CCL 185], HEK 293, KB [CCL 17], Detroit [e.g., Detroit 510, CCL 72] and WI-38 [CCL 75] cells, among others. These cell lines are all available from the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110-2209.

Such E1-expressing cell lines are useful in the generation of recombinant adenovirus E1 deleted vectors. Additionally, or alternatively, cell lines that express one or more adenoviral gene products, e.g., E1A, E1B, E2A, E3 and/or E4, can be constructed using essentially the same procedures as used in the generation of recombinant viral vectors. Such cell lines can be utilised to transcomplement adenovirus vectors deleted in the essential genes that encode those products, or to provide helper functions necessary for packaging of a helper-dependent virus (e.g., adeno-associated virus). The preparation of a host cell involves techniques such as assembly of selected DNA sequences.

In another alternative, the essential adenoviral gene products are provided in trans by the adenoviral vector and/or helper virus. In such an instance, a suitable host cell can be selected from any biological organism, including prokaryotic (e.g., bacterial) cells, and eukaryotic cells, including, insect cells, yeast cells and mammalian cells.

Host cells may be selected from among any mammalian species, including, without limitation, cells such as A549, WEHI, 3T3, 1011/2, HEK 293 cells or Per.C6 (both of which express functional adenoviral El) [Fallaux, 1998], Saos, C2C12, L cells, HT1080, HepG2 and primary fibroblast, hepatocyte and myoblast cells derived from mammals including human, monkey, mouse, rat, rabbit, and hamster.

A particularly suitable complementation cell line is the Procell92 cell line. The Procell92 cell line is based on HEK 293 cells which express adenoviral E1 genes, transfected with the Tet repressor under control of the human phosphoglycerate kinase-1 (PGK) promoter, and the G418-resistance gene (Vitelli et al. PLOS One (2013) 8(e55435):1-9). Procell92.S is adapted for growth in suspension conditions and is useful for producing adenoviral vectors expressing toxic proteins (www.okairos.com/e/inners.php?m=00084, last accessed 13 Apr. 2015).

Assembly of a Viral Particle and Transfection of a Cell Line

Generally, when delivering the vector comprising the minigene by transfection, the vector is delivered in an amount from about 5 μg to about 100 μg DNA, and preferably about 10 to about 50 μg DNA to about 1×104 cells to about 1×1013 cells, and preferably about 105 cells.

However, the relative amounts of vector DNA to host cells may be adjusted, taking into consideration such factors as the selected vector, the delivery method and the host cells selected.

Introduction into the host cell of the vector may be achieved by any means known in the art, including transfection, and infection. One or more of the adenoviral genes may be stably integrated into the genome of the host cell, stably expressed as episomes, or expressed transiently. The gene products may all be expressed transiently, on an episome or stably integrated, or some of the gene products may be expressed stably while others are expressed transiently.

Introduction of vectors into the host cell may also be accomplished using techniques known to the skilled person. Suitably, standard transfection techniques are used, e.g., CaPC transfection or electroporation.

Assembly of the selected DNA sequences of the adenovirus (as well as the transgene and other vector elements) into various intermediate plasmids, and the use of the plasmids and vectors to produce a recombinant viral particle are all achieved using conventional techniques. Such techniques include conventional cloning techniques of cDNA, use of overlapping oligonucleotide sequences of the adenovirus genomes, polymerase chain reaction, and any suitable method which provides the desired nucleotide sequence. Standard transfection and co-transfection techniques are employed, e.g., CaPC precipitation techniques. Other conventional methods employed include homologous recombination of the viral genomes, plaquing of viruses in agar overlay, methods of measuring signal generation, and the like.

For example, following the construction and assembly of the desired minigene-containing viral vector, the vector is transfected in vitro in the presence of a helper virus into the packaging cell line. Homologous recombination occurs between the helper and the vector sequences, which permits the adenovirus-transgene sequences in the vector to be replicated and packaged into virion capsids, resulting in the recombinant viral vector particles. The resulting recombinant adenoviruses are useful in transferring a selected transgene to a selected cell. In in vivo experiments with the recombinant virus grown in the packaging cell lines, the E1-deleted recombinant adenoviral vectors of the invention demonstrate utility in transferring a transgene to a non-simian mammal, preferably a human, cell.

Transgenes

The transgene is a nucleic acid sequence, heterologous to the vector sequences flanking the transgene, which encodes a protein of interest. The nucleic acid coding sequence is operatively linked to regulatory components in a manner which permits transgene transcription, translation, and/or expression in a host cell.

The composition of the transgene sequence will depend upon the use to which the resulting vector will be put. For example, the transgene may be a therapeutic transgene or an immunogenic transgene. Alternatively, a transgene sequence may include a reporter sequence, which upon expression produces a detectable signal. Such reporter sequences include, without limitation, DNA sequences encoding β-lactamase, β-galactosidase (LacZ), alkaline phosphatase, thymidine kinase, green fluorescent protein (GFP), chloramphenicol acetyltransferase (CAT), luciferase, membrane bound proteins including, for example, CD2, CD4, CD8, the influenza hemagglutinin protein, and others well known in the art, to which high affinity antibodies directed thereto exist or can be produced by conventional means, and fusion proteins comprising a membrane bound protein appropriately fused to an antigen tag domain from, among others, hemagglutinin or Myc. These coding sequences, when associated with regulatory elements which drive their expression, provide signals detectable by conventional means, including enzymatic, radiographic, colorimetric, fluorescence or other spectrographic assays, fluorescent activating cell sorting assays and immunological assays, including enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA) and immunohistochemistry.

In one embodiment, the transgene is a non-marker sequence encoding a product which is useful in biology and medicine, such as a therapeutic transgene or an immunogenic transgene such as proteins, RNA, enzymes, or catalytic RNAs. Desirable RNA molecules include tRNA, dsRNA, ribosomal RNA, catalytic RNAs, and antisense RNAs. One example of a useful RNA sequence is a sequence which extinguishes expression of a targeted nucleic acid sequence in the treated animal.

The transgene may be used for treatment, e.g., of genetic deficiencies, as a cancer therapeutic or vaccine, for induction of an immune response, and/or for prophylactic vaccine purposes. As used herein, induction of an immune response refers to the ability of a protein to induce a T cell and/or a humoral immune response to the protein.

Accordingly, in one embodiment the present invention provides a recombinant vector according to the present invention comprising an expression cassette comprising an immunogenic transgene derived from a pathogen. In certain embodiments the pathogen is a respiratory virus. Thus, the present invention provides a recombinant ChAd155-derived adenoviral vector comprising an expression cassette comprising an immunogenic transgene derived from human respiratory syncytial virus (RSV). In one embodiment the recombinant ChAd155-derived adenoviral vector of the present invention comprises an RSV F antigen and RSV M and N antigens. More specifically, the nucleic acid encodes an RSV FΔTM antigen (fusion (F) protein deleted of the transmembrane and cytoplasmic regions), and RSV M2-1 (transcription anti-termination) and N (nucleocapsid) antigens. In certain embodiments, a recombinant vector comprises a nucleic acid sequence (for example within an expression cassette) which encodes a sequence according to SEQ ID NO: 37. In one embodiment, the recombinant vector consists essentially of a polynucleotide having a sequence according to SEQ IS NO: 11.

Regulatory Elements

In addition to the transgene the vector also includes conventional control elements which are operably linked to the transgene in a manner that permits its transcription, translation and/or expression in a cell transfected with the plasmid vector or infected with the virus produced by the invention. As used herein, “operably linked” sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest.

Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation (poly A) signals including rabbit beta-globin polyA; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (e.g., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance secretion of the encoded product. Among other sequences, chimeric introns may be used.

In some embodiments, the Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) (Zuffrey et al. (1999) J Virol; 73(4):2886-9) may be operably linked to the transgene. An exemplary WPRE is provided in SEQ ID NO: 26.

A “promoter” is a nucleotide sequence that permits binding of RNA polymerase and directs the transcription of a gene. Typically, a promoter is located in the 5′ non-coding region of a gene, proximal to the transcriptional start site of the gene. Sequence elements within promoters that function in the initiation of transcription are often characterized by consensus nucleotide sequences. Examples of promoters include, but are not limited to, promoters from bacteria, yeast, plants, viruses, and mammals (including humans). A great number of expression control sequences, including promoters which are internal, native, constitutive, inducible and/or tissue-specific, are known in the art and may be utilized.

Examples of constitutive promoters include, without limitation, the TBG promoter, the retroviral Rous sarcoma virus LTR promoter (optionally with the enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer, see, e.g., Boshart et al, Cell, 41:521-530 (1985)), the CASI promoter, the SV40 promoter, the dihydrofolate reductase promoter, the β-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EF1a promoter (Invitrogen).

In some embodiments, the promoter is a CASI promoter (see, for example, WO2012/115980). The CASI promoter is a synthetic promoter which contains a portion of the CMV enhancer, a portion of the chicken beta-actin promoter, and a portion of the UBC enhancer. In some embodiments, the CASI promoter can include a nucleic acid sequence having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or more, sequence identity to SEQ ID NO: 12. In some embodiments, the promoter comprises or consists of a nucleic acid sequence of SEQ ID NO: 12.

Inducible promoters allow regulation of gene expression and can be regulated by exogenously supplied compounds, environmental factors such as temperature, or the presence of a specific physiological state, e.g., acute phase, a particular differentiation state of the cell, or in replicating cells only. Inducible promoters and inducible systems are available from a variety of commercial sources, including, without limitation, Invitrogen, Clontech and Ariad. Many other systems have been described and can be readily selected by one of skill in the art. For example, inducible promoters include the zinc-inducible sheep metallothionine (MT) promoter and the dexamethasone (Dex)-inducible mouse mammary tumor virus (MMTV) promoter. Other inducible systems include the T7 polymerase promoter system (WO 98/10088); the ecdysone insect promoter (No et al, Proc. Natl. Acad. Sci. USA, 93:3346-3351 (1996)), the tetracycline-repressible system (Gossen et al, Proc. Natl. Acad. Sci. USA, 89:5547-5551 (1992)), the tetracycline-inducible system (Gossen et al, Science, 378:1766-1769 (1995), see also Harvey et al, Curr. Opin. Chem. Biol, 2:512-518 (1998)). Other systems include the FK506 dimer, VP16 or p65 using castradiol, diphenol murislerone, the RU486-inducible system (Wang et al, Nat. Biotech., 15:239-243 (1997) and Wang et al, Gene Ther., 4:432-441 (1997)) and the rapamycin-inducible system (Magari et al, J. Clin. Invest., 100:2865-2872 (1997)). The effectiveness of some inducible promoters increases over time. In such cases one can enhance the effectiveness of such systems by inserting multiple repressors in tandem, e.g., TetR linked to a TetR by an IRES.

In another embodiment, the native promoter for the transgene will be used. The native promoter may be preferred when it is desired that expression of the transgene should mimic the native expression. The native promoter may be used when expression of the transgene must be regulated temporally or developmentally, or in a tissue-specific manner, or in response to specific transcriptional stimuli. In a further embodiment, other native expression control elements, such as enhancer elements, polyadenylation sites or Kozak consensus sequences may also be used to mimic the native expression.

The transgene may be operably linked to a tissue-specific promoter. For instance, if expression in skeletal muscle is desired, a promoter active in muscle should be used. These include the promoters from genes encoding skeletal β-actin, myosin light chain 2A, dystrophin, muscle creatine kinase, as well as synthetic muscle promoters with activities higher than naturally occurring promoters (see Li et al, Nat. Biotech., 17:241-245 (1999)). Examples of promoters that are tissue-specific are known for liver (albumin, Miyatake et al, J. Virol, 71:5124-32 (1997); hepatitis B virus core promoter, Sandig et al, Gene Ther., 3:1002-9 (1996); alpha-fetoprotein (AFP), Arbuthnot et al., Hum. Gene Ther., 7: 1503-14 (1996)), bone osteocalcin (Stein et al, Mol. Biol. Rep., 24:185-96 (1997)); bone sialoprotein (Chen et al., J. Bone Miner. Res., 11:654-64 (1996)), lymphocytes (CD2, Hansal et al, J. Immunol, 161:1063-8 (1998); immunoglobulin heavy chain; T cell receptor chain), neuronal such as neuron-specific enolase (NSE) promoter (Andersen et al, Cell. Mol. Neurobiol, 13:503-15 (1993)), neurofilament light-chain gene (Piccioli et al, Proc. Natl. Acad. Sci. USA, 88:5611-5 (1991)), and the neuron-specific vgf gene (Piccioli et al, Neuron, 15:373-84 (1995)), among others.

Optionally, vectors carrying transgenes encoding therapeutically useful or immunogenic products may also include selectable markers or reporter genes which may include sequences encoding geneticin, hygromicin or purimycin resistance, among others. Such selectable reporters or marker genes (preferably located outside the viral genome to be packaged into a viral particle) can be used to signal the presence of the plasmids in bacterial cells, such as ampicillin resistance. Other components of the vector may include an origin of replication.

These vectors are generated using the techniques and sequences provided herein, in conjunction with techniques known to those of skill in the art. Such techniques include conventional cloning techniques of cDNA such as those described in texts, use of overlapping oligonucleotide sequences of the adenovirus genomes, polymerase chain reaction, and any suitable method which provides the desired nucleotide sequence.

Therapeutics and Prophylaxis

The recombinant ChAd155-based vectors are useful for gene transfer to a human or non-simian mammal in vitro, ex vivo, and in vivo.

The recombinant adenovirus vectors described herein can be used as expression vectors for the production of the products encoded by the heterologous transgenes in vitro. For example, the recombinant replication-incompetent adenovirus containing a transgene may be transfected into a complementation cell line as described above.

A ChAd155-derived recombinant adenoviral vector provides an efficient gene transfer vehicle that can deliver a selected transgene to a selected host cell in vivo or ex vivo even where the organism has neutralizing antibodies to one or more adenovirus serotypes. In one embodiment, the vector and the cells are mixed ex vivo; the infected cells are cultured using conventional methodologies; and the transduced cells are re-infused into the patient. These techniques are particularly well suited to gene delivery for therapeutic purposes and for immunisation, including inducing protective immunity.

Immunogenic Transgenes

The recombinant ChAd155 vectors may also be as administered in immunogenic compositions. An immunogenic composition as described herein is a composition comprising one or more recombinant ChAd155 vector capable of inducing an immune response, for example a humoral (e.g., antibody) and/or cell-mediated (e.g., a cytotoxic T cell) response, against a transgene product delivered by the vector following delivery to a mammal, suitably a human. A recombinant adenovirus may comprise (suitably in any of its gene deletions) a gene encoding a desired immunogen and may therefore be used in a vaccine. The recombinant adenoviruses can be used as prophylactic or therapeutic vaccines against any pathogen for which the antigen(s) crucial for induction of an immune response and able to limit the spread of the pathogen has been identified and for which the cDNA is available.

Accordingly, in one embodiment the present invention provides the use of a recombinant adenovirus according to the present invention in the treatment of disease cause by a pathogen. In one embodiment, such treatment is prophylaxis. In one embodiment, the present invention provides the use of a recombinant adenovirus in the generation of an immune response against a pathogen. In certain embodiments the pathogen is a respiratory virus. Thus, the present invention provides the use of a recombinant ChAd155-derived adenoviral vector comprising an expression cassette comprising an immunogenic transgene derived from human respiratory syncytial virus (RSV) in the treatment or prophylaxis of RSV infection. In one embodiment the recombinant ChAd155-derived adenoviral vector of the present invention comprises an RSV F antigen and RSV M and N antigens. More specifically, the nucleic acid encodes an RSV FΔTM antigen (fusion (F) protein deleted of the transmembrane and cytoplasmic regions), and RSV M2-1 (transcription anti-termination) and N (nucleocapsid) antigens. Particularly, the transgene encodes an RSV antigen as set out in SEQ ID NO: 37.

In further embodiments, the present invention provides the use of a recombinant adenovirus according to the present invention in the manufacture of a medicament for the generation of an immune response against a pathogen. Thus, the present invention provides the use of a recombinant ChAd155-derived adenoviral vector comprising an expression cassette comprising an immunogenic transgene derived from human respiratory syncytial virus (RSV) in the manufacture of a medicament for the treatment or prophylaxis of RSV infection. More specifically, the transgene encodes an RSV FΔTM antigen (fusion (F) protein deleted of the transmembrane and cytoplasmic regions), and RSV M2-1 (transcription anti-termination) and N (nucleocapsid) antigens. Particularly, the transgene encodes an RSV antigen as set out in SEQ ID NO: 37, for example, in one embodiment the trangene comprises a polynucleotide of SEQ ID NO: 11.

In one embodiment the present invention provides a method of treatment or prevention of a disease cause by a pathogen, comprising the administration of an effective amount of a recombinant adenovirus according to the present invention, for example a ChAd155-derived adenovirus, comprising an expression cassette comprising an immunogenic transgene derived from the pathogen. In certain embodiments the pathogen is human respiratory syncytial virus (RSV). In one embodiment the present invention provides a method of generating or enhancing an immune response directed against human respiratory syncytial virus (RSV) comprising the administration of a recombinant adenovirus according to the present invention. Particularly, the method of generating or enhancing an immune response comprises the administration of an effective amount of a ChAd155-derived adenovirus comprising a transgene encoding an RSV antigen as set out in SEQ ID NO: 37, for example, in one embodiment the trangene comprises a polynucleotide of SEQ ID NO: 11.

In one embodiment, the present invention provides an immunogenic composition comprising a recombinant adenovirus according to the present invention, for example a ChAd155-derived adenovirus, including an expression cassette comprising an immunogenic transgene derived from a pathogen, for example human respiratory syncytial virus (RSV), and a pharmaceutically acceptable excipient.

Such vaccine or other immunogenic compositions may be formulated in a suitable delivery vehicle. Generally, doses for the immunogenic compositions are in the range defined below under ‘Delivery Methods and Dosage’. The levels of immunity of the selected gene can be monitored to determine the need, if any, for boosters. Following an assessment of antibody titers in the serum, optional booster immunizations may be desired.

In one embodiment an immunogenic composition comprising a recombinant ChAd155-derived adenoviral vector of the present invention comprising an expression cassette containing a transgene encoding an RSV F antigen and RSV M and N antigens. More specifically, the transgene encodes an RSV FΔTM antigen (fusion (F) protein deleted of the transmembrane and cytoplasmic regions), and RSV M2-1 (transcription anti-termination) and N (nucleocapsid) antigens. Particularly, the transgene encodes an RSV antigen as set out in SEQ ID NO: 37, for example, in one embodiment the trangene comprises a polynucleotide of SEQ ID NO: 11. Optionally, a vaccine or immunogenic composition of the invention may be formulated to contain other components, including, e.g., adjuvants, stabilizers, pH adjusters, preservatives and the like. Examples of suitable adjuvants are provided below under ‘Adjuvants’. Such an adjuvant can be administered with a priming DNA vaccine encoding an antigen to enhance the antigen-specific immune response compared with the immune response generated upon priming with a DNA vaccine encoding the antigen only. Alternatively, such an adjuvant can be administered with a polypeptide antigen which is administered in an administration regimen involving the ChAd155 vectors of the invention (as described below under ‘Administration Regimens’.

The recombinant adenoviruses are administered in an immunogenic amount, that is, an amount of recombinant adenovirus that is effective in a route of administration to transfect the desired target cells and provide sufficient levels of expression of the selected gene to induce an immune response. Where protective immunity is provided, the recombinant adenoviruses are considered to be vaccine compositions useful in preventing infection and/or recurrent disease.

Immunogens expressed by the inventive vectors which are useful to immunize a human or non-human animal against other pathogens include, e.g., bacteria, fungi, parasitic microorganisms or multicellular parasites which infect human and non-human vertebrates, or from a cancer cell or tumor cell. For example, immunogens may be selected from a variety of viral families. Examples of viral families against which an immune response would be desirable include respiratory viruses such as respiratory syncytial virus (RSV) and other paramyxoviruses such as human metapneumovirus, hMPV and parainfluenza viruses (PIV).

Infection with RSV does not confer full protective immunity. Infection in infancy is followed by symptomatic RSV re-infections which continue throughout adulthood. These re-infections generally go undiagnosed because they usually present as common acute upper respiratory tract infections. In more vulnerable persons (e.g., immunocompromised adults or elderly), re-infections can however also lead to severe disease. Both arms of the immune system (humoral and cellular immunity) are involved in protection from severe disease [American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006; 118: 1774-93.

Boukhvalova M S and Blanco J C. The cotton rat Sigmodon hyspidus model of respiratory syncytial virus infection. Curr Top Microbiol Immunol. 2013; 372: 347-58.

Cardenas S, Auais A and Piedimonte G. Palivizumab in the prophylaxis of respiratory syncytial virus infection. Expert Rev Anti Infect Ther. 2005; 3(5): 719-26.

Castilow E M and Varga S M. Overcoming T cell-mediated immunopathology to achieve safe RSV vaccination. Future Virol. 2008; 3(5): 445-454.

Chin J, Magoffin R L, Shearer L A, et al., Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol. 1969; 89(4): 449-63.

Colloca S, Barnes E, Folgori A, et al., Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med. 2012; 4(115): p. 115ra2.

Donnelly M L, Luke G, Mehrotra A, et al., Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip’. J Gen Virol. 2001; 82(Pt 5): 1013-25.

Fallaux, F J et al, (1998), Hum Gene Ther, 9:1909-1917

Guvenel, 2014].

The humoral immune response is capable of neutralizing the virus and inhibiting viral replication, thereby playing a major role in protection against lower respiratory RSV infection and severe disease [American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006; 118: 1774-93.

Boukhvalova M S and Blanco J C. The cotton rat Sigmodon hyspidus model of respiratory syncytial virus infection. Curr Top Microbiol Immunol. 2013; 372: 347-58.

Cardenas S, Auais A and Piedimonte G. Palivizumab in the prophylaxis of respiratory syncytial virus infection. Expert Rev Anti Infect Ther. 2005; 3(5): 719-26.

Castilow E M and Varga S M. Overcoming T cell-mediated immunopathology to achieve safe RSV vaccination. Future Virol. 2008; 3(5): 445-454.

Chin J, Magoffin R L, Shearer L A, et al., Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol. 1969; 89(4): 449-63.

Colloca S, Barnes E, Folgori A, et al., Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med. 2012; 4(115): p. 115ra2.

Donnelly M L, Luke G, Mehrotra A, et al., Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip’. J Gen Virol. 2001; 82(Pt 5): 1013-25.

Fallaux, F J et al, (1998), Hum Gene Ther, 9:1909-1917

Guvenel A K, Chiu C and Openshaw P J. Current concepts and progress in RSV vaccine development. Expert Rev Vaccines. 2014; 13(3): 333-44.

Hertz, M I, Englund J A, Snover D, et al., Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature. Medicine (Baltimore). 1989; 68(5): 269-81.

Kim H W, Canchola J G, Brandt C D et al., Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol. 1969; 89(4): 422-34.

Magro M, Andreu D, Gómez-Puertas P, et al., Neutralization of human respiratory syncytial virus infectivity by antibodies and low-molecular-weight compounds targeted against the fusion glycoprotein. J Virol. 2010; 84(16): 7970-82.

Piedra, 2003]. Passive immunization, in the form of Immunoglobulin G (IgG) RSV-neutralizing monoclonal antibodies (Synagis) given prophylactically, has been shown to prevent RSV disease to some extent in premature infants and newborns with bronchopulmonary dysplasia or underlying cardiopulmonary disease [American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006; 118: 1774-93.

Boukhvalova M S and Blanco J C. The cotton rat Sigmodon hyspidus model of respiratory syncytial virus infection. Curr Top Microbiol Immunol. 2013; 372: 347-58.

Cardenas, 2005].

T cells are also involved in the control of RSV disease. Lethal RSV infections have been described in patients with low CD8 T cells counts, as in the case of severe combined immunodeficiency, bone marrow and lung transplant recipients [Hertz, 1989]. The histopathology of fatal cases of RSV infection of newborns shows that there is a relative paucity of CD8 T cells in the lung infiltrate [Welliver, 2007]. Moreover, the presence of CD8 T cells producing Interferon-gamma (IFN-γ) has been associated with diminished Th2 responses and reduced eosinophilia in animal models of RSV [Castilow, 2008; Stevens, 2009].

The recombinant vectors described herein are expected to be highly efficacious at inducing cytolytic T cells and antibodies directed to the inserted heterologous antigenic protein expressed by the vector.

Suitable antigens of RSV which are useful as immunogens to immunize a human or non-human animal can be selected from: the fusion protein (F), the attachment protein (G), the matrix protein (M2) and the nucleoprotein (N). The term “F protein” or “fusion protein” or “F protein polypeptide” or “fusion protein polypeptide” refers to a polypeptide or protein having all or part of an amino acid sequence of an RSV Fusion protein polypeptide. Similarly, the term “G protein” or “G protein polypeptide” refers to a polypeptide or protein having all or part of an amino acid sequence of an RSV Attachment protein polypeptide. The term “M protein” or “matrix protein” or “M protein polypeptide” refers to a polypeptide or protein having all or part of an amino acid sequence of an RSV Matrix protein and may include either or both of the M2-1 (which may be written herein as M2.1) and M2-2 gene products. Likewise, the term “N protein” or “Nucleocapsid protein” or “N protein polypeptide” refers to a polypeptide or protein having all or part of an amino acid sequence of an RSV Nucleoprotein.

Two groups of human RSV strains have been described, the A and B groups, based mainly on differences in the antigenicity of the G glycoprotein. Numerous strains of RSV have been isolated to date, any of which are suitable in the context of the antigens of the immunogenic combinations disclosed herein. Exemplary strains indicated by GenBank and/or EMBL Accession number can be found in US published application number 2010/0203071 (WO2008114149), which is incorporated herein by reference for the purpose of disclosing the nucleic acid and polypeptide sequences of RSV F and G proteins suitable for use in present invention. In an embodiment, the RSV F protein can be an ectodomain of an RSV F Protein (FΔTM).

Exemplary M and N protein nucleic acids and protein sequences can be found, e.g., in US published application number 2014/0141042 (WO2012/089833), which are incorporated herein for purpose of disclosing the nucleic acid and polypeptide sequences of RSV M and N proteins suitable for use in present invention.

Suitably, for use with in present invention, a transgene nucleic acid encodes an RSV F antigen and RSV M and N antigens. More specifically, the nucleic acid encodes an RSV FΔTM antigen (fusion (F) protein deleted of the transmembrane and cytoplasmic regions), and RSV M2-1 (transcription anti-termination) and N (nucleocapsid) antigens.

Fusion (F) Protein Deleted of the Transmembrane and Cytoplasmic Regions (F0ΔTM)

The RSV F protein is a major surface antigen and mediates viral fusion to target cells. The F protein is an antigen which is highly conserved among RSV subgroups and strains. The F protein is a target for neutralizing antibodies, including the prophylactic RSV-neutralizing monoclonal antibody Synagis. Deletion of the transmembrane region and cytoplasmic tail permits secretion of the FΔTM protein. Neutralizing antibodies including Synagis, that recognize this soluble form of the F protein, inhibit RSV infectivity in vitro [American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006; 118: 1774-93.

Boukhvalova M S and Blanco J C. The cotton rat Sigmodon hyspidus model of respiratory syncytial virus infection. Curr Top Microbiol Immunol. 2013; 372: 347-58.

Cardenas S, Auais A and Piedimonte G. Palivizumab in the prophylaxis of respiratory syncytial virus infection. Expert Rev Anti Infect Ther. 2005; 3(5): 719-26.

Castilow E M and Varga S M. Overcoming T cell-mediated immunopathology to achieve safe RSV vaccination. Future Virol. 2008; 3(5): 445-454.

Chin J, Magoffin R L, Shearer L A, et al., Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol. 1969; 89(4): 449-63.

Colloca S, Barnes E, Folgori A, et al., Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med. 2012; 4(115): p. 115ra2.

Donnelly M L, Luke G, Mehrotra A, et al., Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip’. J Gen Virol. 2001; 82(Pt 5): 1013-25.

Fallaux, F J et al, (1998), Hum Gene Ther, 9:1909-1917

Guvenel A K, Chiu C and Openshaw P J. Current concepts and progress in RSV vaccine development. Expert Rev Vaccines. 2014; 13(3): 333-44.

Hertz, M I, Englund J A, Snover D, et al., Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature. Medicine (Baltimore). 1989; 68(5): 269-81.

Kim H W, Canchola J G, Brandt C D et al., Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol. 1969; 89(4): 422-34.

Magro, 2010].

Nucleocapsid (N) Protein

The N protein is an internal (non-exposed) antigen, highly conserved between RSV strains and known to be a source of many T cell epitopes [Townsend, 1984]. The N protein is essential for the replication and transcription of the RSV genome. The primary function of the N protein is to encapsulate the virus genome for the purposes of RNA transcription, replication and packaging and protects it from ribonucleases.

Transcription Anti-Termination (M2-1) Protein

The M2-1 protein is a transcription anti-termination factor that is important for the efficient synthesis of full-length messenger RNAs (mRNAs) as well as for the synthesis of polycistronic readthrough mRNAs, which are characteristic of non-segmented negative-strand RNA viruses. M2-1 is an internal (non-exposed) antigen, which is highly conserved between RSV strains and known to be a source of many T cell epitopes [Townsend, 1984].

In one embodiment, the present invention provides a recombinant ChAd155 vector comprising a transgene encoding an RSV FΔTM antigen, and RSV M2-1 and N antigens wherein a self-cleavage site is included between the RSV FΔTM antigen and the RSV M2-1 and a flexible linker is included between the RSV M2-1 and N antigens. In one embodiment a suitable transgene nucleic acid encodes the polypeptide represented by SEQ ID NO:37

In one embodiment, the immunogen may be from a retrovirus, for example a lentivirus such as the Human Immunodeficiency Virus (HIV). In such an embodiment, immunogens may be derived from HIV-1 or HIV-2.

The HIV genome encodes a number of different proteins, each of which can be immunogenic in its entirety or as a fragment when expressed by vectors of the present invention. Envelope proteins include gp120, gp41 and Env precursor gp160, for example. Non-envelope proteins of HIV include for example internal structural proteins such as the products of the gag and pol genes and other non-structural proteins such as Rev, Nef, Vif and Tat. In an embodiment the vector of the invention encodes one or more polypeptides comprising HIV Gag.

The Gag gene is translated as a precursor polyprotein that is cleaved by protease to yield products that include the matrix protein (p17), the capsid (p24), the nucleocapsid (p9), p6 and two space peptides, p2 and p1, all of which are examples of fragments of Gag.

The Gag gene gives rise to the 55-kilodalton (kD) Gag precursor protein, also called p55, which is expressed from the unspliced viral mRNA. During translation, the N terminus of p55 is myristoylated, triggering its association with the cytoplasmic aspect of cell membranes. The membrane-associated Gag polyprotein recruits two copies of the viral genomic RNA along with other viral and cellular proteins that triggers the budding of the viral particle from the surface of an infected cell. After budding, p55 is cleaved by the virally encoded protease (a product of the pol gene) during the process of viral maturation into four smaller proteins designated MA (matrix [p17]), CA (capsid [p24]), NC (nucleocapsid [p9]), and p6, all of which are examples of fragments of Gag. In one embodiment, the vectors of the present invention comprise a Gag polypeptide of SEQ ID NO: 38.

Adjuvants

An “adjuvant” as used herein refers to a composition that enhances the immune response to an immunogen. Examples of such adjuvants include but are not limited to inorganic adjuvants (e.g. inorganic metal salts such as aluminium phosphate or aluminium hydroxide), organic adjuvants (e.g. saponins, such as QS21, or squalene), oil-based adjuvants (e.g. Freund's complete adjuvant and Freund's incomplete adjuvant), cytokines (e.g. IL-1β, IL-2, IL-7, IL-12, IL-18, GM-CFS, and INF-γ) particulate adjuvants (e.g. immuno-stimulatory complexes (ISCOMS), liposomes, or biodegradable microspheres), virosomes, bacterial adjuvants (e.g. monophosphoryl lipid A, such as 3-de-O-acylated monophosphoryl lipid A (3D-MPL), or muramyl peptides), synthetic adjuvants (e.g. non-ionic block copolymers, muramyl peptide analogues, or synthetic lipid A), synthetic polynucleotides adjuvants (e.g polyarginine or polylysine) and immunostimulatory oligonucleotides containing unmethylated CpG dinucleotides (“CpG”).

One suitable adjuvant is monophosphoryl lipid A (MPL), in particular 3-de-O-acylated monophosphoryl lipid A (3D-MPL). Chemically it is often supplied as a mixture of 3-de-O-acylated monophosphoryl lipid A with either 4, 5, or 6 acylated chains. It can be purified and prepared by the methods taught in GB 2122204B, which reference also discloses the preparation of diphosphoryl lipid A, and 3-O-deacylated variants thereof. Other purified and synthetic lipopolysaccharides have been described (U.S. Pat. No. 6,005,099 and EP 0 729 473 B1; Hilgers et al., 1986, Int. Arch. Allergy. Immunol., 79(4):392-6; Hilgers et al., 1987, Immunology, 60(1):141-6; and EP 0 549 074 B11).

Saponins are also suitable adjuvants (see Lacaille-Dubois, M and Wagner H, A review of the biological and pharmacological activities of saponins. Phytomedicine vol 2 pp 363-386 (1996)). For example, the saponin Quil A (derived from the bark of the South American tree Quillaja Saponaria Molina), and fractions thereof, are described in U.S. Pat. No. 5,057,540 and Kensil, Crit. Rev. Ther. Drug Carrier Syst., 1996, 12:1-55; and EP 0 362 279 B1. Purified fractions of Quil A are also known as immunostimulants, such as QS21 and QS17; methods of their production is disclosed in U.S. Pat. No. 5,057,540 and EP 0 362 279 B1. Also described in these references is QS7 (a non-haemolytic fraction of Quil-A). Use of QS21 is further described in Kensil et al. (1991, J. Immunology, 146: 431-437). Combinations of QS21 and polysorbate or cyclodextrin are also known (WO 99/10008). Particulate adjuvant systems comprising fractions of QuilA, such as QS21 and QS7 are described in WO 96/33739 and WO 96/11711.

Another adjuvant is an immunostimulatory oligonucleotide containing unmethylated CpG dinucleotides (“CpG”) (Krieg, Nature 374:546 (1995)). CpG is an abbreviation for cytosine-guanosine dinucleotide motifs present in DNA. CpG is known as an adjuvant when administered by both systemic and mucosal routes (WO 96/02555, EP 468520, Davis et al, J. Immunol, 1998, 160:870-876; McCluskie and Davis, J. Immunol., 1998, 161:4463-6). CpG, when formulated into vaccines, may be administered in free solution together with free antigen (WO 96/02555) or covalently conjugated to an antigen (WO 98/16247), or formulated with a carrier such as aluminium hydroxide (Brazolot-Millan et al., Proc. Natl. Acad. Sci., USA, 1998, 95:15553-8).

Adjuvants such as those described above may be formulated together with carriers, such as liposomes, oil in water emulsions, and/or metallic salts (including aluminum salts such as aluminum hydroxide). For example, 3D-MPL may be formulated with aluminum hydroxide (EP 0 689 454) or oil in water emulsions (WO 95/17210); QS21 may be formulated with cholesterol containing liposomes (WO 96/33739), oil in water emulsions (WO 95/17210) or alum (WO 98/15287); CpG may be formulated with alum (Brazolot-Millan, supra) or with other cationic carriers.

Combinations of adjuvants may be utilized in the present invention, in particular a combination of a monophosphoryl lipid A and a saponin derivative (see, e.g., WO 94/00153; WO 95/17210; WO 96/33739; WO 98/56414; WO 99/12565; WO 99/11241), more particularly the combination of QS21 and 3D-MPL as disclosed in WO 94/00153, or a composition where the QS21 is quenched in cholesterol-containing liposomes (DQ) as disclosed in WO 96/33739. Alternatively, a combination of CpG plus a saponin such as QS21 is an adjuvant suitable for use in the present invention. A potent adjuvant formulation involving QS21, 3D-MPL & tocopherol in an oil in water emulsion is described in WO 95/17210 and is another formulation for use in the present invention. Saponin adjuvants may be formulated in a liposome and combined with an immunostimulatory oligonucleotide. Thus, suitable adjuvant systems include, for example, a combination of monophosphoryl lipid A, preferably 3D-MPL, together with an aluminium salt (e.g. as described in WO00/23105). A further exemplary adjuvant comprises comprises QS21 and/or MPL and/or CpG. QS21 may be quenched in cholesterol-containing liposomes as disclosed in WO 96/33739.

Other suitable adjuvants include alkyl Glucosaminide phosphates (AGPs) such as those disclosed in WO9850399 or U.S. Pat. No. 6,303,347 (processes for preparation of AGPs are also disclosed), or pharmaceutically acceptable salts of AGPs as disclosed in U.S. Pat. No. 6,764,840. Some AGPs are TLR4 agonists, and some are TLR4 antagonists. Both are thought to be useful as adjuvants.

It has been found (WO 2007/062656, which published as US 2011/0293704 and is incorporated by reference for the purpose of disclosing invariant chain sequences) that the fusion of the invariant chain to an antigen which is comprised by an expression system used for vaccination increases the immune response against said antigen, if it is administered with an adenovirus. Accordingly, in one embodiment of the invention, the immunogenic transgene may be co-expressed with invariant chain in a recombinant ChAd155 viral vector.

In another embodiment, the invention provides the use of the capsid of ChAd155 (optionally an intact or recombinant viral particle or an empty capsid is used) to induce an immunomodulatory effect response, or to enhance or adjuvant a cytotoxic T cell response to another active agent by delivering a ChAd155 capsid to a subject. The ChAd155 capsid can be delivered alone or in a combination regimen with an active agent to enhance the immune response thereto. Advantageously, the desired effect can be accomplished without infecting the host with an adenovirus.

Administration Regimens

Commonly, the ChAd155 recombinant adenoviral vectors will be utilized for delivery of therapeutic or immunogenic molecules (such as proteins). It will be readily understood for both applications, that the recombinant adenoviral vectors of the invention are particularly well suited for use in regimens involving repeat delivery of recombinant adenoviral vectors. Such regimens typically involve delivery of a series of viral vectors in which the viral capsids are alternated. The viral capsids may be changed for each subsequent administration, or after a pre-selected number of administrations of a particular serotype capsid (e.g. one, two, three, four or more). Thus, a regimen may involve delivery of a recombinant adenovirus with a first capsid, delivery with a recombinant adenovirus with a second capsid, and delivery with a recombinant adenovirus with a third capsid. A variety of other regimens which use the adenovirus capsids of the invention alone, in combination with one another, or in combination with other adenoviruses (which are preferably immunologically non-crossreactive) will be apparent to those of skill in the art. Optionally, such a regimen may involve administration of recombinant adenovirus with capsids of other non-human primate adenoviruses, human adenoviruses, or artificial sequences such as are described herein.

The adenoviral vectors of the invention are particularly well suited for therapeutic regimens in which multiple adenoviral-mediated deliveries of transgenes are desired, e.g., in regimens involving redelivery of the same transgene or in combination regimens involving delivery of other transgenes. Such regimens may involve administration of a ChAd155 adenoviral vector, followed by re-administration with a vector from the same serotype adenovirus. Particularly desirable regimens involve administration of a ChAd155 adenoviral vector, in which the source of the adenoviral capsid sequences of the vector delivered in the first administration differs from the source of adenoviral capsid sequences of the viral vector utilized in one or more of the subsequent administrations. For example, a therapeutic regimen involves administration of a ChAd155 vector and repeat administration with one or more adenoviral vectors of the same or different serotypes.

In another example, a therapeutic regimen involves administration of an adenoviral vector followed by repeat administration with a ChAd155 vector which has a capsid which differs from the source of the capsid in the first delivered adenoviral vector, and optionally further administration with another vector which is the same or, preferably, differs from the source of the adenoviral capsid of the vector in the prior administration steps. These regimens may deliver the same or different therapeutic or immunogenic molecules. These regimens are not limited to delivery of adenoviral vectors constructed using the ChAd155 sequences. Rather, these regimens can readily utilize other adenoviral sequences, including, without limitation, other adenoviral sequences including other non-human primate adenoviral sequences, or human adenoviral sequences, in combination with the ChAd155 vectors.

In a further example, a therapeutic regimen may involve either simultaneous (such as co-administration) or sequential (such as a prime-boost) delivery of (i) one or more ChAd155 adenoviral vectors and (ii) a further component such as non-adenoviral vectors, non-viral vectors, and/or a variety of other therapeutically useful compounds or molecules such as antigenic proteins optionally simultaneously administered with adjuvant. These regimens may deliver the same or different therapeutic or immunogenic molecules. Examples of co-administration include homo-lateral co-administration and contra-lateral co-administration (further described below under ‘Delivery Methods and Dosage’).

Suitable non-adenoviral vectors for use in simultaneous or particularly in sequential delivery (such as prime-boost) with one or more ChAd155 adenoviral vectors include one or more poxviral vectors. Suitably, the poxviral vector belongs to the subfamily chordopoxvirinae, more suitably to a genus in said subfamily selected from the group consisting of orthopox, parapox, yatapox, avipox (suitably canarypox (ALVAC) or fowlpox (FPV)) and molluscipox. Even more suitably, the poxviral vector belongs to the orthopox and is selected from the group consisting of vaccinia virus, NYVAC (derived from the Copenhagen strain of vaccinia), Modified Vaccinia Ankara (MVA), cowpoxvirus and monkeypox virus. Most suitably, the poxviral vector is MVA.

“Simultaneous” administration suitably refers to the same ongoing immune response. Preferably both components are administered at the same time (such as simultaneous administration of both DNA and protein), however, one component could be administered within a few minutes (for example, at the same medical appointment or doctor's visit), within a few hours. Such administration is also referred to as co-administration. In some embodiments, co-administration may refer to the administration of an adenoviral vector, an adjuvant and a protein component. In other embodiments, co-administration refers to the administration of an adenoviral vector and another viral vector, for example a second adenoviral vector or a poxvirus such as MVA. In other embodiments, co-administration refers to the administration of an adenoviral vector and a protein component, which is optionally adjuvanted.

In another embodiment, a therapeutic regimen involves the administration of an immunogenic composition to a pregnant mother and subsequent administration of a further immunogenic composition to the infant after birth, for example 1, 2, 3, 4, 5, 6, 7 or 8 months after birth. Antibodies generated as a result of the maternal immunisation can cross the placenta to provide passive immunisation of the gestational infant. In one embodiment the maternal immunisation is by administration of a recombinant protein antigen and the infant immunisation is by administration of a recombinant adenoviral vector according to the present invention. In another embodiment the maternal immunisation is by administration of a recombinant adenoviral vector according to the present invention and the infant immunisation is by administration of a recombinant protein antigen. In another embodiment both the maternal and infant immunisation is by administration of a recombinant adenoviral vector according to the present invention.

Thus, the present invention provides the use of a recombinant ChAd155-derived adenoviral vector according to the present invention in the generation of an immune response against RSV in an infant, particularly an infant born to a mother immunised against RSV during pregnancy. Accordingly, the present invention provides the use of a recombinant ChAd155-derived adenoviral vector comprising an immunogenic transgene derived from human respiratory syncytial virus (RSV) in the manufacture of a medicament for the generation of an immune response in an infant. Desirably, particularly the infant born to a mother immunised against RSV during her pregnancy. More specifically, the transgene encodes an RSV FΔTM antigen (fusion (F) protein deleted of the transmembrane and cytoplasmic regions), and RSV M2-1 (transcription anti-termination) and N (nucleocapsid) antigens. Particularly, the transgene encodes an RSV antigen as set out in SEQ ID NO: 37, for example, in one embodiment the trangene comprises a polynucleotide of SEQ ID NO: 11.

A prime-boost regimen may be used. Prime-boost refers to two separate immune responses in the same individual: (i) an initial priming of the immune system followed by (ii) a secondary or boosting of the immune system many weeks or months after the primary immune response has been established.

Such a regimen may involve the administration of a recombinant ChAd155 vector to prime the immune system to second, booster, administration with a traditional antigen, such as a protein (optionally co-administered with adjuvant), or a recombinant virus carrying the sequences encoding such an antigen (e.g., WO 00/11140). Alternatively, an immunization regimen may involve the administration of a recombinant ChAd155 vector to boost the immune response to a vector (either viral or DNA-based) encoding an antigen. In another alternative, an immunization regimen involves administration of a protein followed by booster with a recombinant ChAd155 vector encoding the antigen. In one example, the prime-boost regimen can provide a protective immune response to the virus, bacteria or other organism from which the antigen is derived. In another embodiment, the prime-boost regimen provides a therapeutic effect that can be measured using conventional assays for detection of the presence of the condition for which therapy is being administered.

Preferably, a boosting composition is administered about 2 to about 27 weeks after administering the priming composition to the subject. The administration of the boosting composition is accomplished using an effective amount of a boosting composition containing or capable of delivering the same antigen or a different antigen as administered by the priming vaccine. The boosting composition may be composed of a recombinant viral vector derived from the same viral source or from another source. Alternatively, the boosting composition can be a composition containing the same antigen as encoded in the priming vaccine, but in the form of a protein, which composition induces an immune response in the host. The primary requirements of the boosting composition are that the antigen of the composition is the same antigen, or a cross-reactive antigen, as that encoded by the priming composition.

Delivery Methods and Dosage

The vector may be prepared for administration by being suspended or dissolved in a pharmaceutically or physiologically acceptable carrier such as isotonic saline; isotonic salts solution or other formulations that will be apparent to those skilled in the art. The appropriate carrier will be evident to those skilled in the art and will depend in large part upon the route of administration. The compositions described herein may be administered to a mammal in a sustained release formulation using a biodegradable biocompatible polymer, or by on-site delivery using micelles, gels and liposomes.

In some embodiments, the recombinant adenovirus of the invention is administered to a subject by intramuscular injection, intravaginal injection, intravenous injection, intraperitoneal injection, subcutaneous injection, epicutaneous administration, intradermal administration, nasal administration or oral administration.

If the therapeutic regimen involves co-administration of one or more ChAd155 adenoviral vectors and a further component, each formulated in different compositions, they are favourably administered co-locationally at or near the same site. For example, the components can be administered (e.g. via an administration route selected from intramuscular, transdermal, intradermal, sub-cutaneous) to the same side or extremity (“co-lateral” administration) or to opposite sides or extremities (“contra-lateral” administration).

Dosages of the viral vector will depend primarily on factors such as the condition being treated, the age, weight and health of the patient, and may thus vary among patients. For example, a therapeutically effective adult human or veterinary dosage of the viral vector generally contains 1×105 to 1×1015 viral particles, such as from 1×108 to 1×1012 (e.g., 1×108, 2.5×108, 5×108, 1×109, 1.5×109, 2.5×109, 5×109, 1×1010, 1.5×1010, 2.5×1010, 5×1010, 1×1011 1.5×1011, 2.5×1011, 5×1011, 1×1012 particles). Alternatively, a viral vector can be administered at a dose that is typically from 1×105 to 1×1010 plaque forming units (PFU), such as 1×105 PFU, 2.5×105 PFU, 5×105 PFU, 1×106 PFU, 2.5×106 PFU, 5×106 PFU, 1×107 PFU, 2.5×107 PFU, 5×107 PFU, 1×108 PFU, 2.5×108 PFU, 5×108 PFU, 1×109 PFU, 2.5×109 PFU, 5×109 PFU, or 1×1010 PFU. Dosages will vary depending upon the size of the animal and the route of administration. For example, a suitable human or veterinary dosage (for about an 80 kg animal) for intramuscular injection is in the range of about 1×109 to about 5×1012 particles per mL, for a single site. Optionally, multiple sites of administration may be used. In another example, a suitable human or veterinary dosage may be in the range of about 1×1011 to about 1×1015 particles for an oral formulation.

The viral vector can be quantified by Quantitative PCR Analysis (Q-PCR), for example with primers and probe designed on CMV promoter region using as standard curve serial dilution of plasmid DNA containing the vector genome with expression cassette including HCMV promoter. The copy number in the test sample is determined by the parallel line analysis method. Alternative methods for vector particle quantification can be analytical HPLC or spectrophotometric method based on A260 nm.

An immunologically effective amount of a nucleic acid may suitably be between 1 ng and 100 mg. For example, a suitable amount can be from 1 μg to 100 mg. An appropriate amount of the particular nucleic acid (e.g., vector) can readily be determined by those of skill in the art. Exemplary effective amounts of a nucleic acid component can be between 1 ng and 100 μg, such as between 1 ng and 1 μg (e.g., 100 ng-1 μg), or between1 μg and 100 μg, such as 10 ng, 50 ng, 100 ng, 150 ng, 200 ng, 250 ng, 500 ng, 750 ng, or 1 μg. Effective amounts of a nucleic acid can also include from 1 μg to 500 μg, such as between 1 μg and 200 μg, such as between 10 and 100 μg, for example 1 μg, 2 μg, 5 μg, 10 μg, 20 μg, 50 μg, 75 μg, 100 μg, 150 μg, or 200 μg. Alternatively, an exemplary effective amount of a nucleic acid can be between 100 μg and 1 mg, such as from 100 μg to 500 μg, for example, 100 μg, 150 μg, 200 μg, 250 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg or 1 mg.

Generally a human dose will be in a volume of between 0.1 ml and 2 ml. Thus the composition described herein can be formulated in a volume of, for example 0.1, 0.15, 0.2, 0.5, 1.0, 1.5 or 2.0 ml human dose per individual or combined immunogenic components.

One of skill in the art may adjust these doses, depending on the route of administration and the therapeutic or vaccine application for which the recombinant vector is employed. The levels of expression of the transgene, or for an adjuvant, the level of circulating antibody, can be monitored to determine the frequency of dosage administration.

If one or more priming and/or boosting steps are used, this step may include a single dose that is administered hourly, daily, weekly or monthly, or yearly. As an example, mammals may receive one or two doses containing between about 10 μg to about 50 μg of plasmid in carrier.

The amount or site of delivery is desirably selected based upon the identity and condition of the mammal.

The therapeutic levels of, or level of immune response against, the protein encoded by the selected transgene can be monitored to determine the need, if any, for boosters. Following an assessment of CD8+ T cell response, or optionally, antibody titers, in the serum, optional booster immunizations may be desired. Optionally, the recombinant ChAd155 vectors may be delivered in a single administration or in various combination regimens, e.g., in combination with a regimen or course of treatment involving other active ingredients or in a prime-boost regimen.

The present invention will now be further described by means of the following non-limiting examples.

EXAMPLES Example 1: Isolation of ChAd155

Wild type chimpanzee adenovirus type 155 (ChAd155) was isolated from a healthy young chimpanzee housed at the New Iberia Research Center facility (New Iberia Research Center; The University of Louisiana at Lafayette) using standard procedures as described in Colloca et al. (2012) and WO 2010086189, which is hereby incorporated by reference for the purpose of describing adenoviral isolation and characterization techniques

Example 2: ChAd155 Vector Construction

The ChAd155 viral genome was then cloned in a plasmid or in a BAC vector and subsequently modified (FIG. 2) to carry the following modifications in different regions of the ChAd155 viral genome:

a) deletion of the E1 region (from bp 449 to bp 3529) of the viral genome;

b) deletion of the E4 region (from bp 34731 to bp 37449) of the viral genome;

c) insertion of the E4orf6 derived from human AdS.

2.1: Deletion of E1 Region: Construction of BAC/ChAd155 ΔE1 TetO hCMV RpsL-Kana #1375

The ChAd155 viral genome was cloned into a BAC vector by homologous recombination in E. coli strain BJ5183 electroporation competent cells (Stratagene catalog no. 2000154) co-transformed with ChAd155 viral DNA and Subgroup C BAC Shuttle (#1365). As shown in the schematic of FIG. 3, the Subgroup C Shuttle is a BAC vector derived from pBeloBAC11 (GenBank U51113, NEB) and which is dedicated to the cloning of ChAd belonging to species C and therefore contains the pIX gene and DNA fragments derived from right and left ends (including right and left ITRs) of species C ChAd viruses.

The Species C BAC Shuttle also contains a RpsL-Kana cassette inserted between left end and the pIX gene. In addition, an Amp-LacZ-SacB selection cassette, flanked by ISceI restriction sites, is present between the pIX gene and right end of the viral genome. In particular, the BAC Shuttle comprised the following features: Left ITR: bp 27 to 139, hCMV(tetO) RpsL-Kana cassette: bp 493 to 3396, pIX gene: bp 3508 to 3972, ISceI restriction sites: bp 3990 and 7481, Amp-LacZ-SacB selection cassette: bp 4000 to 7471, Right ITR: bp 7805 to 7917.

BJ5183 cells were co-transformed by electroporation with ChAd155 purified viral DNA and Subgroup C BAC Shuttle vector digested with ISceI restriction enzyme and then purified from gel. Homologous recombination occurring between pIX gene and right ITR sequences (present at the ends of Species C BAC Shuttle linearized DNA) and homologous sequences present in ChAd155 viral DNA lead to the insertion of ChAd155 viral genomic DNA in the BAC shuttle vector. At the same time, the viral E1 region was deleted and substituted by the RpsL-Kana cassette, generating BAC/ChAd155 ΔE1/TetO hCMV RpsL-Kana #1375.

2.2: Plasmid Construction by Homologous Recombination in E. coli BJ5183

2.2.1: Deletion of E4 Region—Construction of pChAd155 ΔE1, E4_Ad5E4orf6/TetO hCMV RpsL-Kana (#1434)

To improve propagation of the vector, a deletion of the E4 region spanning from nucleotide 34731-37449 (ChAd155 wild type sequence) was introduced in the vector backbone by replacing the native E4 region with Ad5 E4orf6 coding sequence using a strategy involving several steps of cloning and homologous recombination in E. coli. The E4 coding region was completely deleted while the E4 native promoter and polyadenylation signal were conserved. To this end, a shuttle vector was constructed to allow the insertion of Ad5orf6 by replacing the ChAd155 native E4 region by homologous recombination in E. coli BJ5183 as detailed below.

Construction of pARS SpeciesC Ad5E4orf6-1

A DNA fragment containing Ad5orf6 was obtained by PCR using Ad5 DNA as template, with the oligonucleotides 5′-ATACGGACTAGTGGAGAAGTACTCGCCTACATG-3′ (SEQ ID NO: 13) and 5′-ATACGGAAGATCTAAGACTTCAGGAAATATGACTAC-3′ (SEQ ID NO: 14). The PCR fragment was digested with BgIII and SpeI and cloned into Species C RLD-EGFP shuttle digested with BgIII and SpeI, generating the plasmid pARS Species C Ad5orf6-1. Details regarding the shuttle can be found in Colloca et al, Sci. Transl. Med. (2012) 4:115ra.

Construction of pARS SpeciesC Ad5E4orf6-2

To delete the E4 region, a 177 bp DNA fragment spanning bp 34586 to bp 34730 of the ChAd155 wt sequence (SEQ ID NO: 10) was amplified by PCR using the plasmid BAC/ChAd155 ΔE1_TetO hCMV RpsL-Kana (#1375) as a template with the following oligonucleotides: 5′-ATTCAGTGTACAGGCGCGCCAAAGCATGACGCTGTTGATTTGATTC-3′ (SEQ ID NO: 15) and 5′-ACTAGGACTAGTTATAAGCTAGAATGGGGCTTTGC-3′ (SEQ ID NO: 16). The PCR fragment was digested with BsrGI and SpeI and cloned into pARS SubGroupC Ad5orf6-1 digested with BsrGI and SpeI, generating the plasmid pARS SpeciesC Ad5orf6-2 (#1490). A schematic diagram of this shuttle plasmid is provided in FIG. 4. In particular, the shuttle plasmid comprised the following features: Left ITR: bp 1 to 113, Species C first 460bp: bp 1 to 460, ChAd155 wt (bp 34587 to bp 34724 of SEQ ID NO:10): bp 516 to 650, Ad5 orf6: bp 680 and 1561, Species C last 393 bp: bp 1567 to 1969, Right ITR: bp 1857 to 1969.

Construction of pChAd155 ΔE1, E4_Ad5E4orf6/TetO hCMV RpsL-Kana (#1434)

The resulting plasmid pARS SubGroupC Ad5orf6-2 was then used to replace the E4 region within the ChAd155 backbone with Ad5orf6. To this end the plasmid BAC/ChAd155 ΔE1_TetO hCMV RpsL-Kana (#1375) was digested with PacI/PmeI and co-transformed into BJ5183 cells with the digested plasmid pARS SubGroupC Ad5orf6-2 BsrGI/AscI, to obtain the pChAd155 ΔE1, E4_Ad5E4orf6/TetO hCMV RpsL-Kana (#1434) pre-adeno plasmid.

2.2.2: Insertion of RSV Expression Cassette—Construction of pChAd155 ΔE1, E4_Ad5E4orf6/TetO hCMV RSV

The vaccine antigens are computational consensus sequences derived from the alignment of many different subgroup A RSV isolates retrieved from the National Centre for Biotechnology Information (NCBI) database. For each antigen the protein consensus sequence was derived using Multiple Sequence Comparison by Log-Expectation (MUSCLE) version 3.6 by alignment of all non-identical sequences and applying the majority rule. When blasted, the derived consensus sequence of the F protein was found to differ by only one amino acid from a natural annotated variant: embCAA26143.1. The consensus N protein also had only one amino acid different from the annotated variant ID:1494470, while the M2-1 protein was identical to the variant P04545. Finally, each antigenic sequence was codon-optimized for expression in eukaryotic cells, chemically synthesized and assembled. The construct, shown in FIG. 14 and SEQ ID NO: 37 contains the aphtovirus Foot and Mouth Disease Virus 2A region (18 amino acids) between the soluble F protein FΔTM and the other two RSV antigens, which mediates polyprotein processing by a translational effect known as ribosomal skip [American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006; 118: 1774-93.

Boukhvalova M S and Blanco J C. The cotton rat Sigmodon hyspidus model of respiratory syncytial virus infection. Curr Top Microbiol Immunol. 2013; 372: 347-58.

Cardenas S, Auais A and Piedimonte G. Palivizumab in the prophylaxis of respiratory syncytial virus infection. Expert Rev Anti Infect Ther. 2005; 3(5): 719-26.

Castilow E M and Varga S M. Overcoming T cell-mediated immunopathology to achieve safe RSV vaccination. Future Virol. 2008; 3(5): 445-454.

Chin J, Magoffin R L, Shearer L A, et al., Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol. 1969; 89(4): 449-63.

Colloca S, Barnes E, Folgori A, et al., Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med. 2012; 4(115): p. 115ra2.

Donnelly, 2001]. After transfection into mammalian cells, cleavage occurs and the soluble F protein is detected in the cell culture supernatant. The fusion protein N-M2-1 is instead expressed and detected in the intracellular fraction.

An RSV cassette was cloned into a linearised pre-adeno acceptor vector via homologous recombination in E. coli by exploiting the homology existing between HCMV promoter and BGH polyA sequences. The plasmid pvjTetOhCMV-bghpolyA_RSV was cleaved with SfiI and SpeI to excise the 4.65 Kb fragment containing the HCMV promoter with tetO, RSV and BGHpolyA sequence. The resulting RSV 4.65 Kb fragment was cloned by homologous recombination into the pChAd155 ΔE1, E4_Ad5E4orf6/TetO hCMV RpsL-Kana (#1434) acceptor vector carrying the RpsL-Kana selection cassette under control of HCMV and BGHpA. The acceptor pre-adeno plasmid was linearized with the restriction endonuclease SnaBI. The resulting construct was the pChAd155 ΔE1, E4_Ad5E4orf6/TetO hCMV RSV vector (FIG. 5).

2.3: BAC Vector Construction by Recombineering

2.3.1: Deletion of E4 Region—Construction of BAC/ChAd155 ΔE1, E4_Ad5E4orf6/TetO hCMV RpsL-Kana #1390

A deletion of the E4 region spanning from nucleotide 34731-37449 of the ChAd155 wt sequence was introduced in the vector backbone by replacing this native E4 region with the Ad5 E4orf6 coding sequence using a strategy involving two different steps of recombineering in E. coli SW102 competent cells.

The first step resulted in insertion of a selection cassette including the suicide gene SacB, ampicillin-R gene and lacZ (Amp-LacZ-SacB selection cassette) in the E4 region of ChAd155, for the purpose of positive/negative selection of recombinants.

First Step—Substitution of ChAd155 Native E4 Region with Amp-LacZ-SacB Selection Cassette

The Amp-LacZ-SacB selection cassette was amplified by PCR using the oligonucleotides provided below containing E4 flanking sequences to allow homologous recombination:

1021-FW E4 Del Stepl (SEQ ID NO: 17) (5′- TTAATAGACACAGTAGCTTAATAGACCCAGTAGTGCAAAGCCCCATTCTA GCTTATAACCCCTATTTGTTTATTTTTCT-3′) and 1022-RW E4 Del Step1 (SEQ ID NO: 18) (5′- ATATATACTCTCTCGGCACTTGGCCTTTTACACTGCGAAGTGTTGGTGCT GGTGCTGCGTTGAGAGATCTTTATTTGTTAACTGTTAATTGTC-3′).

The PCR product was used to transform E. coli SW102 competent cells containing the pAdeno plasmid BAC/ChAd155 (DE1) tetO hCMV—RpsLKana #1375. The transformation of SW102 cells allowed the insertion of the selection cassette in the E4 region of ChAd155 via lambda (λ) Red-mediated homologous recombination, thus obtaining BAC/ChAd155 (DE1) TetOhCMV—RpsL Kana #1379 (including Amp-LacZ-SacB cassette by substituting ChAd155 native E4 region).

Second Step—Substitution of Amp-IacZ-SacB Selection Cassette with Ad5E4orf6 Region

The resulting plasmid BAC/ChAd155 (DE1) TetOhCMV—RpsL Kana #1379 (with Amp-LacZ-SacB cassette in place of ChAd155 E4 region) was then manipulated to replace the Amp-lacZ-SacB selection cassette with Ad5orf6 within the ChAd155 backbone. To this end, a DNA fragment containing the Ad5orf6 region was obtained by PCR, using the oligonucleotides 1025-FW E4 Del Step2 (5′-TTAATAGACACAGTAGCTTAATA-3′) (SEQ ID NO: 19) and 1026-RW E4 Del Step2 (5′-GGAAGGGAGTGTCTAGTGTT-3′) (SEQ ID NO: 20). The resulting DNA fragment was introduced into E. coli SW102 competent cells containing the pAdeno plasmid BAC/ChAd155 (DE1) TetOhCMV—RpsL Kana) #1379, resulting in a final plasmid BAC/ChAd155 (DE1, E4 Ad5E4orf6) TetOhCMV—RpsL Kana #1390 containing Ad5orf6 substituting the native ChAd155 E4 region.

2.3.2: Insertion of RSV Expression Cassette: Construction of BAC/ChAd155 ΔE1, E4_Ad5E4orf6/TetOhCMV RSV #1393

An RSV transgene was cloned into the BAC/ChAd155 ΔE1, E4_Ad5E4orf6/TetOhCMV RpsL Kana #1390 vector by substituting the RpsL-Kana selection cassette. The construction strategy was based on two different steps of recombineering in E. coli SW102 competent cells.

First Step—Substitution of RpsL-Kana Cassette with Amp-LacZ-SacB Selection Cassette

The Amp-LacZ-SacB selection cassette was obtained from plasmid BAC/ChAd155 (DE1) TetO hCMV Amp-LacZ-SacB #1342 by PCR using the oligonucleotides 91-SubMonte FW (5′-CAATGGGCGTGGATAGCGGTTTGAC-3′) (SEQ ID NO: 21) and 890-BghPolyA RW (5′-CAGCATGCCTGCTATTGTC-3′) (SEQ ID NO: 22). The product was transformed into E. coli SW102 competent cells containing the pAdeno plasmid BAC/ChAd155 (DE1, E4 Ad5E4orf6) TetOhCMV—RpsL Kana #1390, resulting in BAC/ChAd155 (DE1, E4 Ad5E4orf6) TetOhCMV—Amp-LacZ-SacB #1386.

Second Step—Substitution of Amp-lacZ-SacB Selection Cassette with RSV Transgene

The RSV transgene was inserted in plasmid BAC/ChAd155 (DE1, E4 Ad5E4orf6) TetOhCMV—Amp-LacZ-SacB #1386 by replacing the Amp-lacZ-SacB selection cassette by homologous recombination. To this end, the plasmid pvjTetOhCMV-bghpolyA_RSV #1080 (containing an RSV expression cassette) was cleaved with SpeI and SfiI to excise the 4.4 Kb fragment including the HCMV promoter, RSV and BGHpolyA. The resulting RSV 4.4 Kb fragment was transformed into E. coli SW102 competent cells containing the pAdeno plasmid BAC/ChAd155 (DE1, E4 Adr5E4orf6) TetOhCMV—Amp-LacZ-SacB #1386, resulting in the final plasmid BAC/ChAd155 ΔE1, E4_Ad5E4orf6/TetO hCMV RSV #1393. The structure of the BAC carrying ChAd155/RSV (SEQ ID NO: 11) is illustrated in FIG. 6. In particular, ChAd155/RSV comprised the following features: Species C Left ITR: bp 1 to 113, hCMV(tetO) bp 467 to 1311, RSV gene: bp 1348 to 4785, bghpolyA: by 4815 to 5032, Ad5E4orf6: bp 36270 to 37151, Species C Right ITR: bp 37447 to 37559.

Example 3: Vector Production

The productivity of ChAd155 was evaluated in comparison to ChAd3 and PanAd3 in the Procell 92 cell line.

3.1: Production of Vectors comprising an HIV Gag Transgene

Vectors expressing the HIV Gag protein were prepared as described above (ChAd155/GAG) or previously (ChAd3/GAG Colloca et al, Sci. Transl. Med. (2012) 4:115ra). ChAd3/GAG and ChAd155/GAG were rescued and amplified in Procell 92 until passages 3 (P3); P3 lysates were used to infect 2 T75 flasks of Procell 92 cultivated in monolayer with each vector. A multiplicity of infection (MOI) of 100 vp/cell was used for both infection experiments. The infected cells were harvested when full CPE was evident (72 hours post-infection) and pooled; the viruses were released from the infected cells by 3 cycles of freeze/thaw (−70°/37° C.) then the lysate was clarified by centrifugation. The clarified lysates were quantified by Quantitative PCR Analysis with primers and probe complementary to the CMV promoter region. The oligonucleotide sequences are the following: CMVfor 5′-CATCTACGTATTAGTCATCGCTATTACCA-3′ (SEQ ID NO: 23), CMVrev 5′-GACTTGGAAATCCCCGTGAGT-3′ (SEQ ID NO: 24), CMVFAM-TAMRA probe 5′-ACATCAATGGGCGTGGATAGCGGTT-3′ (SEQ ID NO: 25) (QPCRs were run on ABI Prism 7900 Sequence detector—Applied Biosystem). The resulting volumetric titers (vp/ml) measured on clarified lysates and the specific productivity expressed in virus particles per cell (vp/cell) are provided in Table 1 below and illustrated in FIG. 7.

TABLE 1 Vector productivity from P3 lysates. Total vp Vector vp/ml (20 ml conc.) vp/cell ChAd3/GAG 9.82E+09 1.96E+11 6.61E+03 ChAd155/GAG 1.11E+10 2.22E+11 7.46E+03

To confirm the higher productivity of the ChAd155 vector expressing HIV Gag transgene, a second experiment was performed by using purified viruses as inoculum. To this end, Procell 92 cells were seeded in a T25 Flask and infected with ChAd3/GAG and ChAd155/GAG when the confluence of the cells was about 80%, using a MOI=100 vp/cell of infection. The infected cells were harvested when full CPE was evident; the viruses were released from the infected cells by freeze/thaw and clarified by centrifugation. The clarified lysates were quantified by Quantitative PCR Analysis by using following primers and probe: CMVfor 5′-CATCTACGTATTAGTCATCGCTATTACCA-3′ (SEQ ID NO: 23), CMV rev GACTTGGAAATCCCCGTGAGT (SEQ ID NO: 24), CMV FAM-TAMRA probe 5′-ACATCAATGGGCGTGGATAGCGGTT-3′ (SEQ ID NO: 25) complementary to the CMV promoter region (samples were analysed on an ABI Prism 7900 Sequence detector—Applied Biosystems). The resulting volumetric titers (vp/ml) measured on clarified lysates and the specific productivity expressed in virus particles per cell (vp/cell) are provided in Table 2 below and illustrated in FIG. 8.

TABLE 2 Vector productivity from purified viruses. Total vp/T25 flask Vector vp/ml (5 ml of lysate) vp/cell ChAd3/GAG 1.00E+10 5.00E+10 1.67E+04 ChAd155/GAG 1.21E+10 6.05E+10 2.02E+04

3.2: Production of Vectors comprising an RSV Transgene

A different set of experiments were performed to evaluate the productivity of RSV vaccine vectors in Procell 92.S cultivated in suspension. The experiment compared PanAd3/RSV (described in WO2012/089833) and Chad155/RSV in parallel by infecting Procell 92.S at a cell density of 5×105 cells/ml. The infected cells were harvested 3 days post infection; the virus was released from the infected cells by 3 cycles of freeze/thaw and the lysate was clarified by centrifugation. The clarified lysates were then quantified by Quantitative PCR Analysis as reported above. The volumetric productivity and the cell specific productivity are provided in Table 3 below and illustrated in FIG. 9.

TABLE 3 Volumetric Cell specific productivity productivity Virus (Vp/ml) Total vp (vp/cell) PanAd3/RSV 5.82E+09 2.91E+11 1.16E+4  ChAd155/RSV 3.16E+10 1.58E+12 6.31E+04

Example 4: Transgene Expression Levels

4.1: Expression Level of HIV Gag Transgene

Expression levels were compared in parallel experiments by infecting HeLa cells with ChAd3 and ChAd155 vectors comprising an HIV Gag transgene. HeLa cells were seeded in 24 well plates and infected in duplicate with ChAd3/GAG and ChAd155/GAG purified viruses using a MOI=250 vp/cell. The supernatants of HeLa infected cells were harvested 48 hours post-infection, and the production of secreted HIV GAG protein was quantified by using a commercial ELISA Kit (HIV-1 p24 ELISA Kit, PerkinElmer Life Science). The quantification was performed according to the manufacturer's instruction by using an HIV-1 p24 antigen standard curve. The results, expressed in pg/ml of GAG protein, are illustrated in FIG. 10.

4.1: Expression Level of RSV F Transgene

Expression levels were compared in parallel experiments by infecting HeLa cells with the above-described PanAd3 and ChAd155 vectors comprising an RSV F transgene. To this end, HeLa cells were seeded in 6 well plates and infected in duplicate with PanAd3/RSV and ChAd155/RSV purified viruses using a MOI=500 vp/cell. The supernatants were harvested 48 hours post-infection, and the production of secreted RSV F protein was quantified by ELISA. Five different dilutions of the supernatants were transferred to microplate wells which are coated with a commercial mouse anti-RSV F monoclonal antibody. The captured antigen was revealed using a secondary anti-RSV F rabbit antiserum followed by Biotin-conjugated anti-rabbit IgG, then by adding Streptavidin-AP conjugate (BD Pharmingen cat. 554065). The quantification was performed by using an RSV F protein (Sino Biological cat. 11049-V08B) standard curve. The results obtained, expressed as ug/ml of RSV F protein, are provided in Table 4 below.

TABLE 4 Sample μg/ml RSV F protein ChAd155/RSV 5.9 PanAd3/RSV 4

A western blot analysis was also performed to confirm the higher level of transgene expression provided by the ChAd155 RSV vector relative to the PanAd3 RSV vector. HeLa cells plated in 6 well plates were infected with PanAd3/RSV and ChAd155/RSV purified viruses using MOI=250 and 500 vp/cell. The supernatants of HeLa infected cells were harvested and the production of secreted RSV F protein were analysed by non-reducing SDS gel followed by Western Blot analysis. Equivalent quantities of supernatants were loaded on non-reducing SDS gel; after electrophoresis separation, the proteins were transferred to a nitrocellulose membrane to be probed with an anti-RSV F mouse monoclonal antibody (clone RSV-F-3 catalog no: ABIN308230 available at antibodies-online.com (last accessed 13 Apr. 2015). After the incubation with primary antibody, the membrane was washed and then incubated with anti-mouse HRP conjugate secondary antibody. Finally the assay was developed by electrochemiluminescence using standard techniques (ECL detection reagents Pierce catalog no W3252282). The Western Blot results are shown in FIG. 11. A band of about 170 kD indicated by the arrow was revealed by monoclonal antibody mAb 13 raised against the F protein, which corresponds to the expected weight of trimeric F protein. It can be seen that the ChAd155 RSV vector produced a darker band at both MOI=250 and 500 vp/cell.

Example 5: Evaluation of Immunological Potency by Mouse Immunization Experiments

5.1: Immunogenicity of Vectors comprising the HIV Gag Transgene

The immunogenicity of the ChAd155/GAG vector was evaluated in parallel with the ChAd3/GAG vector in BALB/c mice (5 per group). The experiment was performed by injecting 106 viral particles intramuscularly. T-cell response was measured 3 weeks after the immunization by ex vivo IFN-gamma enzyme-linked immunospot (ELISpot) using a GAG CD8+ T cell epitope mapped in BALB/c mice. The results are shown in FIG. 12, expressed as IFN-gamma Spot Forming Cells (SFC) per million of splenocytes. Each dot represents the response in a single mouse, and the line corresponds to the mean for each dose group. Injected dose in number of virus particles and frequency of positive mice to the CD8 immunodominant peptide are shown on the x axis.

5.2 Immunogenicity of Vectors comprising the RSV Transgene

Preclinical studies to evaluate the immunogenicity of the vaccine candidate ChAd155-RSV were performed in inbred BALB/c mice (5.2.1). The vaccine efficacy was also evaluated in cotton rats after intranasal (IN) challenge with RSV through measurement of viral load in lower (lung) or upper (nasal tissue) respiratory tract (5.2.2). Finally, the vaccine was tested in young seronegative calves, which is a model that mimics natural RSV infection (5.2.3).

5.2.1—Inbred Mice

ChAd155-RSV was tested in the BALB/c mouse strain to evaluate its immunological potency. Dose escalation in inbred mice is the standard assay that has enabled the ranking of chimpanzee adenoviral vectors immunological potency in mice with results that have been confirmed consistently across species (non-human primates and humans) [Colloca, 2012].

The immunological potency of the PanAd3/RSV and ChAd155/RSV vectors was evaluated in BALB/c mice. Both vectors were injected intramuscularly at doses of 3×106, 107, and 108 vp. Three weeks after vaccination the splenocytes of immunized mice were isolated and analyzed by IFN-gamma-ELISpot using as antigens immunodominant peptide F and M epitopes mapped in BALB/c mice. The levels of immune-responses were reduced in line with decreasing dosage (as expected) but immune responses were clearly higher in the groups of mice immunized with ChAd155/RSV vector compared to the equivalent groups of mice immunized with PanAd3/RSV vaccine (FIG. 13). In FIG. 13, symbols show individual mouse data, expressed as IFN-gamma Spot Forming Cells (SFC)/million splenocytes, calculated as the sum of responses to the three immunodominant epitopes (F51-66 F85-93 and M2-1282-290) and corrected for background. Horizontal lines represent the mean number of IFN-gamma SFC/million splenocytes for each dose group. A T cell dose response was observed in ChAd155-RSV immunized mice with all mice responding even at the low 3×106 vp dosage. PanAd3-RSV induced comparable responses at the highest dosage, while ChAd155-RSV induced higher responses at the two lower dosages (FIG. 13).

In a second study, a group of BALB/c mice received ChAd155-RSV and another group received PanAd3-RSV, IM at a single dose of 5×108 vp. The mice (n=5/group) were subsequently bled every two weeks starting from Week 4 post-vaccination up to Week 10, to monitor induction and maintenance of anti F antibodies. Pooled sera from immunized mice were tested in Enzyme-Linked Immunosorbent Assay (ELISA) on coated RSV-F protein. FIG. 15 shows RSV F Immunoglobulin G (IgG) titers, measured by ELISA in pooled sera from immunized mice at different time points from vaccination. Pooled sera serial dilutions were plated in RSV-F protein coated ELISA wells, and the binding of specific IgG revealed using a goat anti-mouse IgG conjugated to Alkaline Phosphatase (AP) and p-Nitrophenyl Phosphate (pNPP) substrate. The reaction was allowed to proceed over time and read at 405 nanometres (nm) during fixed time points. Data are expressed as endpoint titers calculated as the dilution of serum giving an optical density (OD)405 reading greater than three Standard Deviations (SDs) above the mean of pre-immune sera at a 1:100 dilution. Antibody responses to RSV F protein were induced by ChAd155-RSV and maintained over a period of 10 weeks after a single IM administration of 5×108 vp, and antibody titers were 1.5-fold higher at plateau than those induced by PanAd3-RSV (FIG. 15).

5.2.2—Cotton Rats

Methodology

Five groups of female, 6-8 weeks old cotton rats (8 rats/group) were immunized by the intramusculat (IM) route with 5×108 or 5×107 vp of ChAd155-RSV or PanAd3-RSV (see Table 5). A control group was left unvaccinated. Seven weeks after vaccination, the animals were challenged by intranasal (IN) inoculation with a 105 pfu standard dose of RSV A (Long strain). Five days after challenge, the animals were sacrificed, the nasal tissue harvested for viral titration, and the lung en bloc collected and bisected for viral titration (left lobes) and histopathology (right lobes, Groups A, D, E only). RSV titers in nasal tissue or lung homogenates collected five days after RSV challenge were determined by a standard plaque assay on permissive cells (HEp-2 cells). FFPE lung sections were stained with Hematoxylin/Eosin. Four parameters of pulmonary inflammation were evaluated: peribronchiolitis (PB), perivasculitis (PV), interstitial pneumonia (IP), and alveolitis (A). Slides were scored blind on a 0-4 severity scale, and values were then converted to a 0-100% histopathology score. The animals were also bled at Day 0 and at the time of challenge, for RSV neutralizing antibody titration by standard plaque assay on permissive cells (Vero cells). Neutralizing antibody titers were determined as the reciprocal of the serum dilutions at which 60% of the virus was neutralized compared to virus control.

TABLE 5 Dosing scheme of cotton rats Group Vaccine Immunization dose A Control — B PanAd3-RSV IM 5 × 108 vp C PanAd3-RSV IM 5 × 107 vp D ChAd155-RSV IM 5 × 108 vp E ChAd155-RSV IM 5 × 107 vp

Immunogenicity and Efficacy Results

FIG. 16 panels A and B show the RSV viral titers from nasal tissue and lung homogenates, respectively, by plaque assay. RSV titers in nasal tissue or lung homogenates collected five days after RSV challenge were determined by a standard plaque assay on permissive cells. Data are expressed as RSV plaque forming units per gram of tissue (pfu/g). intramuscular ChAd155-RSV at both dosages completely abolished viral replication in the lung, apart from one animal at the lowest dosage. Infection of the upper respiratory tract was also significantly reduced (between 1 and 2 logs lower RSV titers recovered from nasal tissue) in a dose-dependent manner compared to unvaccinated control animals.

It has been previously shown that in cotton rats a serum neutralizing antibody titer of 1:100 or greater confers protection from viral replication in the lung [Prince, 1985]. In this study both vectors administered IM at 5×108 vp induced RSV neutralizing antibodies in the range of the protective threshold while titers decreased with a lower vaccine dosage (FIG. 16 panel C). Nevertheless, the vaccination prevented viral replication in the lung even when serum antibody levels were below 1:100, suggesting a role for other immune effector mechanisms. RSV neutralizing antibody titers are expressed as the serum dilution reducing plaques by 60% compared to control.

Safety Results

Lung histopathology was performed five days post-infection to assess whether vaccination with ChAd155-RSV induced vaccine-enhanced pathology. Four parameters of pulmonary inflammation were evaluated according to the presence of inflammatory cells in different areas of the lung structure: peribronchiolitis (PB, inflammatory cell infiltration around the bronchioles), perivasculitis (PV, inflammatory cell infiltration around the small blood vessels), interstitial pneumonia (IP, inflammatory cell infiltration and thickening of alveolar walls), and alveolitis (A, cells within the alveolar space). Formalin-fixed, paraffin-embedded lung sections were stained with Hematoxylin/Eosin. Slides were scored blind on a 0-4 severity scale, and values were then converted to a 0-100% histopathology score. The dashed line (set at 5%) represents the threshold for significant pathology. Histopathology data for PanAd3-RSV (depicted in grey) derive from a previous study. Among the four parameters, the presence of inflammatory infiltrate in the alveolar walls (interstitial pneumonia [IP]), and more importantly in the alveolar space, (alveolitis [A]), is considered predictive for enhanced disease and lung pathology [Prince, 2001]. The results of the lung histopathology analysis (FIG. 16 panel D) showed that IM ChAd155-RSV did not induce significant IP and A pathology scores. The low levels of IP and A observed were consistent with what has been observed during RSV acute infection and secondary RSV re-infection [American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006; 118: 1774-93.

Boukhvalova, 2013], and were comparable to values observed with PanAd3-RSV in previous studies.

In FIG. 16, dashed horizontal lines represent limit of detection (LOD) for each assay in panels A, B and C. In panel D The dashed horizontal line (set at 5%) represents the threshold for significant pathology.

5.2.3—Seronegative Calves

Bovine RSV (bRSV) causes respiratory disease in young calves that is very similar to that observed in human infants. In addition, bovine RSV is genetically and antigenically related to human RSV. The newborn calf bRSV model a relevant animal model for evaluation of safety of human RSV vaccines

Methodology

Three groups of five colostrum-restricted calves were vaccinated on two occasions, four weeks apart, with 5×1010 vp ChAd155-RSV or comparator PanAd3-RSV, as indicated in Table 6.

TABLE 6 Dosing scheme of newborn calves Group Vaccination 1 Dose Vaccination 2 Dose A PanAd3-RSV IM 5 × 1010 vp PanAd3-RSV IM 5 × 1010 vp B ChAd155-RSV IM 5 × 1010 vp ChAd155-RSV IM 5 × 1010 vp C PanAd3-control IM 5 × 1010 vp PanAd3-control IM 5 × 1010 vp

Group C was mock-vaccinated with PanAd3 adenovectors containing unrelated antigens. The animals were challenged four weeks after the second vaccination by IN (10 mL) and intratracheal (IT) (10 mL) administration of 104 pfu of bRSV Snook strain. Six days after the infection, when the virus replication peaked in the lung and in the nose causing maximal pulmonary pathology, the animals were sacrificed. In this model, due to the IN/IT routes of administration of the challenge inoculum, very few, if any, clinical signs are observed in challenged control animals. Therefore, the effects of vaccination on bRSV challenge were studied by nasopharyngeal excretion of bRSV, analysis of levels of bRSV in lung homogenate, development of gross pneumonic lesions and analysis of leukocytes in broncho-alveolar lavage (BAL). Antibody responses (antibody and neutralizing titers) induced after vaccination and/or challenge were also investigated.

Immunogenicity Results

Effect of Vaccination on Induction of bRSV-Specific Serum IgG

Kinetics of the mean bRSV-specific serum IgG antibody and human RSV (hRSV) neutralizing titers throughout the course of the vaccination are shown per study group in FIG. 17. The graph shows the geometric mean value of each study group. Levels of bRSV-specific IgG were determined using bRSV (Snook strain)-infected fetal calf kidney (FCK) cell lysate as antigen [Taylor, 1995]. A lysate of mock-infected FCK cells was used as a control antigen.

Two out of five animals in each group receiving an RSV immunogen showed low levels of maternal bRSV-specific antibodies at the start of the vaccination. Nevertheless, all animals responded to the vaccines and reached high levels (log10=3-3.5) of bRSV-specific antibodies after the boost (FIG. 17A). All the calves in the control group had detectable bRSV-specific antibodies at the start of the vaccination which declined during the study and were not detectable on the day of the challenge. In conclusion, PanAd3-RSV and ChAd155-RSV displayed similar potency in eliciting antibody responses.

No hRSV neutralizing response could be detected before vaccination. After a single dose, all animals vaccinated with PanAd3-RSV and 2 out of 5 animals vaccinated with ChAd155-RSV had measurable RSV neutralizing antibodies (FIG. 17B). A marked boost was observed after the second dose for both vaccines. No further enhancement of the hRSV neutralizing response was observed 1 week after challenge.

Efficacy Results

Effect of Vaccination on Nasopharyngeal Excretion of bRSV

Following bRSV challenge, nasopharynx swabs were obtained daily and the bRSV titers within the samples determined. As shown in FIG. 18, titers in the control group increased from day 3 to day 6. bRSV replication appeared to be significantly reduced in calves that had received either of the adenovector RSV constructs.

Effect of Vaccination on Replication of bRSV in the Lower Respiratory Tract.

Six days after bRSV challenge, high titers of bRSV were detected in lung wash cells (LWC) and lung lobe homogenates (RA, RC and LC) of all of the control calves, and from tracheal scrape (TSc) samples in 5 out of 6 of the control calves (FIG. 19). In contrast, bRSV was detected at low titers from the TSc samples of 2 and from LWC of 1 of the calves which received ChAd155-RSV, while it was undetectable in all samples from the calves which received PanAd3-RSV.

Effect of Vaccination on Pulmonary Pathology

Six days after bRSV challenge, extensive gross pneumonic consolidation was observed in 6 out of 6 control calves (FIG. 20). In contrast, there was little or no gross pneumonic consolidation in the calves that had received either of the adenovector RSV constructs. FIG. 21 quantifies the mean proportion±SD of lymphocytes (L), macrophages (Mo), polymorphonuclear leukocytes (PMN) and eosinophils (Eo) in BAL, 6 days after bRSV challenge. Approximately 70% of the cells in BAL from control calves were PMN. A lower proportion of PMN was found in BAL from calves which received ChAd155-RSV or PanAd3-RSV, indicating a reduced pulmonary inflammation. Importantly, eosinophils were very few or undetectable in the lungs of calves which received ChAd155-RSV or PanAd3-RSV suggesting the absence of vaccine-induced disease exacerbation.

Conclusion

Taken together the results reported above demonstrated that ChAd155 is an improved adenoviral vector in comparison to ChAd3 and PanAd3 vectors. ChAd155 was shown to be more productive therefore facilitating the manufacture process, able to express higher level of transgene in vitro and also in vivo providing a stronger T-cell response and at least as potent an antibody response against the antigens expressed in animal models. Protective immunity is achieved without signs of vaccine-induced enhanced pulmonary pathology.

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DESCRIPTION OF THE SEQUENCES Polypeptide sequence of ChAd155 fiber SEQ ID NO: 1 MKRTKTSDESFNPVYPYDTESGPPSVPFLTPPFVSPDGFQESPPGVLSLNLAEPLVTSHGMLALKMGSGLS LDDAGNLTSQDITTASPPLKKTKTNLSLETSSPLTVSTSGALTVAAAAPLAVAGTSLTMQSEAPLTVQDAK LTLATKGPLTVSEGKLALQTSAPLTAADSSTLTVSATPPLSTSNGSLGIDMQAPIYTTNGKLGLNFGAPLH VVDSLNALTVVTGQGLTINGTALQTRVSGALNYDTSGNLELRAAGGMRVDANGQLILDVAYPFDAQNN LSLRLGQGPLFVNSAHNLDVNYNRGLYLFTSGNTKKLEVNIKTAKGLIYDDTAIAINAGDGLQFDSGSDT NPLKTKLGLGLDYDSSRAIIAKLGTGLSFDNTGAITVGNKNDDKLTLWTTPDPSPNCRIYSEKDAKFTLVL TKCGSQVLASVSVLSVKGSLAPISGTVTSAQIVLRFDENGVLLSNSSLDPQYWNYRKGDLTEGTAYTNAV GFMPNLTAYPKTQSQTAKSNIVSQVYLNGDKSKPMTLTITLNGTNETGDATVSTYSMSFSWNWNGSNYI NETFQTNSFTFSYIAQE Polynucleotide sequence encoding ChAd155 fiber SEQ ID NO: 2 ATGAAGCGCACCAAAACGTCTGACGAGAGCTTCAACCCCGTGTACCCCTATGACACGGAAAGCGGCC CTCCCTCCGTCCCTTTCCTCACCCCTCCCTTCGTGTCTCCCGATGGATTCCAAGAAAGTCCCCCCGGGG TCCTGTCTCTGAACCTGGCCGAGCCCCTGGTCACTTCCCACGGCATGCTCGCCCTGAAAATGGGAAGT GGCCTCTCCCTGGACGACGCTGGCAACCTCACCTCTCAAGATATCACCACCGCTAGCCCTCCCCTCAA AAAAACCAAGACCAACCTCAGCCTAGAAACCTCATCCCCCCTAACTGTGAGCACCTCAGGCGCCCTC ACCGTAGCAGCCGCCGCTCCCCTGGCGGTGGCCGGCACCTCCCTCACCATGCAATCAGAGGCCCCCC TGACAGTACAGGATGCAAAACTCACCCTGGCCACCAAAGGCCCCCTGACCGTGTCTGAAGGCAAACT GGCCTTGCAAACATCGGCCCCGCTGACGGCCGCTGACAGCAGCACCCTCACAGTCAGTGCCACACCA CCCCTTAGCACAAGCAATGGCAGCTTGGGTATTGACATGCAAGCCCCCATTTACACCACCAATGGAA AACTAGGACTTAACTTTGGCGCTCCCCTGCATGTGGTAGACAGCCTAAATGCACTGACTGTAGTTACT GGCCAAGGTCTTACGATAAACGGAACAGCCCTACAAACTAGAGTCTCAGGTGCCCTCAACTATGACA CATCAGGAAACCTAGAATTGAGAGCTGCAGGGGGTATGCGAGTTGATGCAAATGGTCAACTTATCCT TGATGTAGCTTACCCATTTGATGCACAAAACAATCTCAGCCTTAGGCTTGGACAGGGACCCCTGTTTG TTAACTCTGCCCACAACTTGGATGTTAACTACAACAGAGGCCTCTACCTGTTCACATCTGGAAATACC AAAAAGCTAGAAGTTAATATCAAAACAGCCAAGGGTCTCATTTATGATGACACTGCTATAGCAATCA ATGCGGGTGATGGGCTACAGTTTGACTCAGGCTCAGATACAAATCCATTAAAAACTAAACTTGGATT AGGACTGGATTATGACTCCAGCAGAGCCATAATTGCTAAACTGGGAACTGGCCTAAGCTTTGACAAC ACAGGTGCCATCACAGTAGGCAACAAAAATGATGACAAGCTTACCTTGTGGACCACACCAGACCCAT CCCCTAACTGTAGAATCTATTCAGAGAAAGATGCTAAATTCACACTTGTTTTGACTAAATGCGGCAGT CAGGTGTTGGCCAGCGTTTCTGTTTTATCTGTAAAAGGTAGCCTTGCGCCCATCAGTGGCACAGTAAC TAGTGCTCAGATTGTCCTCAGATTTGATGAAAATGGAGTTCTACTAAGCAATTCTTCCCTTGACCCTC AATACTGGAACTACAGAAAAGGTGACCTTACAGAGGGCACTGCATATACCAACGCAGTGGGATTTAT GCCCAACCTCACAGCATACCCAAAAACACAGAGCCAAACTGCTAAAAGCAACATTGTAAGTCAGGTT TACTTGAATGGGGACAAATCCAAACCCATGACCCTCACCATTACCCTCAATGGAACTAATGAAACAG GAGATGCCACAGTAAGCACTTACTCCATGTCATTCTCATGGAACTGGAATGGAAGTAATTACATTAA TGAAACGTTCCAAACCAACTCCTTCACCTTCTCCTACATCGCCCAAGAA Polypeptide sequence of ChAd155 penton SEQ ID NO: 3 MRRAAMYQEGPPPSYESVVGAAAAAPSSPFASQLLEPPYVPPRYLRPTGGRNSIRYSELAPLFDTTRVYLV DNKSADVASLNYQNDHSNFLTTVIQNNDYSPSEASTQTINLDDRSHWGGDLKTILHTNMPNVNEFMFTN KFKARVMVSRSHTKEDRVELKYEWVEFELPEGNYSETMTIDLMNNAIVEHYLKVGRQNGVLESDIGVKF DTRNFRLGLDPVTGLVMPGVYTNEAFHPDIILLPGCGVDFTYSRLSNLLGIRKRQPFQEGFRITYEDLEGG NIPALLDVEAYQDSLKENEAGQEDTAPAASAAAEQGEDAADTAAADGAEADPAMVVEAPEQEEDMNDS AVRGDTFVTRGEEKQAEAEAAAEEKQLAAAAAAAALAAAEAESEGTKPAKEPVIKPLTEDSKKRSYNLL KDSTNTAYRSWYLAYNYGDPSTGVRSWTLLCTPDVTCGSEQVYWSLPDMMQDPVTFRSTRQVSNFPVV GAELLPVHSKSFYNDQAVYSQLIRQFTSLTHVFNRFPENQILARPPAPTITTVSENVPALTDHGTLPLRNSIG GVQRVTVTDARRRTCPYVYKALGIVSPRVLSSRTF Polynucleotide sequence encoding ChAd155 penton SEQ ID NO: 4 ATGCGGCGCGCGGCGATGTACCAGGAGGGACCTCCTCCCTCTTACGAGAGCGTGGTGGGCGCGGCGG CGGCGGCGCCCTCTTCTCCCTTTGCGTCGCAGCTGCTGGAGCCGCCGTACGTGCCTCCGCGCTACCTG CGGCCTACGGGGGGGAGAAACAGCATCCGTTACTCGGAGCTGGCGCCCCTGTTCGACACCACCCGGG TGTACCTGGTGGACAACAAGTCGGCGGACGTGGCCTCCCTGAACTACCAGAACGACCACAGCAATTT TTTGACCACGGTCATCCAGAACAATGACTACAGCCCGAGCGAGGCCAGCACCCAGACCATCAATCTG GATGACCGGTCGCACTGGGGCGGCGACCTGAAAACCATCCTGCACACCAACATGCCCAACGTGAAC GAGTTCATGTTCACCAATAAGTTCAAGGCGCGGGTGATGGTGTCGCGCTCGCACACCAAGGAAGACC GGGTGGAGCTGAAGTACGAGTGGGTGGAGTTCGAGCTGCCAGAGGGCAACTACTCCGAGACCATGA CCATTGACCTGATGAACAACGCGATCGTGGAGCACTATCTGAAAGTGGGCAGGCAGAACGGGGTCCT GGAGAGCGACATCGGGGTCAAGTTCGACACCAGGAACTTCCGCCTGGGGCTGGACCCCGTGACCGG GCTGGTTATGCCCGGGGTGTACACCAACGAGGCCTTCCATCCCGACATCATCCTGCTGCCCGGCTGCG GGGTGGACTTCACTTACAGCCGCCTGAGCAACCTCCTGGGCATCCGCAAGCGGCAGCCCTTCCAGGA GGGCTTCAGGATCACCTACGAGGACCTGGAGGGGGGCAACATCCCCGCGCTCCTCGATGTGGAGGCC TACCAGGATAGCTTGAAGGAAAATGAGGCGGGACAGGAGGATACCGCCCCCGCCGCCTCCGCCGCC GCCGAGCAGGGCGAGGATGCTGCTGACACCGCGGCCGCGGACGGGGCAGAGGCCGACCCCGCTATG GTGGTGGAGGCTCCCGAGCAGGAGGAGGACATGAATGACAGTGCGGTGCGCGGAGACACCTTCGTC ACCCGGGGGGAGGAAAAGCAAGCGGAGGCCGAGGCCGCGGCCGAGGAAAAGCAACTGGCGGCAGC AGCGGCGGCGGCGGCGTTGGCCGCGGCGGAGGCTGAGTCTGAGGGGACCAAGCCCGCCAAGGAGCC CGTGATTAAGCCCCTGACCGAAGATAGCAAGAAGCGCAGTTACAACCTGCTCAAGGACAGCACCAA CACCGCGTACCGCAGCTGGTACCTGGCCTACAACTACGGCGACCCGTCGACGGGGGTGCGCTCCTGG ACCCTGCTGTGCACGCCGGACGTGACCTGCGGCTCGGAGCAGGTGTACTGGTCGCTGCCCGACATGA TGCAAGACCCCGTGACCTTCCGCTCCACGCGGCAGGTCAGCAACTTCCCGGTGGTGGGCGCCGAGCT GCTGCCCGTGCACTCCAAGAGCTTCTACAACGACCAGGCCGTCTACTCCCAGCTCATCCGCCAGTTCA CCTCTCTGACCCACGTGTTCAATCGCTTTCCTGAGAACCAGATTCTGGCGCGCCCGCCCGCCCCCACC ATCACCACCGTCAGTGAAAACGTTCCTGCTCTCACAGATCACGGGACGCTACCGCTGCGCAACAGCA TCGGAGGAGTCCAGCGAGTGACCGTTACTGACGCCAGACGCCGCACCTGCCCCTACGTTTACAAGGC CTTGGGCATAGTCTCGCCGCGCGTCCTTTCCAGCCGCACTTTT Polypeptide sequence of ChAd155 hexon SEQ ID NO: 5 MATPSMMPQWSYMHISGQDASEYLSPGLVQFARATDSYFSLSNKFRNPTVAPTHDVTTDRSQRLTLRFIP VDREDTAYSYKARFTLAVGDNRVLDMASTYFDIRGVLDRGPTFKPYSGTAYNSLAPKGAPNSCEWEQEE TQTAEEAQDEEEDEAEAEEEMPQEEQAPVKKTHVYAQAPLSGEKITKDGLQIGTDATATEQKPIYADPTF QPEPQIGESQWNEADASVAGGRVLKKTTPMKPCYGSYARPTNANGGQGVLVEKDGGKMESQVDMQFFS TSENARNEANNIQPKLVLYSEDVHMETPDTHISYKPAKSDDNSKVMLGQQSMPNRPNYIGFRDNFIGLMY YNSTGNMGVLAGQASQLNAVVDLQDRNTELSYQLLLDSMGDRTRYFSMWNQAVDSYDPDVRIIENHGT EDELPNYCFPLGGIGVTDTYQAIKTNGNGNGGGNTTWTKDETFADRNEIGVGNNFAMEINLSANLWRNF LYSNVALYLPDKLKYNPSNVEISDNPNTYDYMNKRVVAPGLVDCYINLGARWSLDYMDNVNPFNHHRN AGLRYRSMLLGNGRYVPFHIQVPQKFFAIKNLLLLPGSYTYEWNFRKDVNMVLQSSLGNDLRVDGASIKF ESICLYATFFPMAHNTASTLEAMLRNDTNDQSFNDYLSAANMLYPIPANATNVPISIPSRNWAAFRGWAF TRLKTKETPSLGSGFDPYYTYSGSIPYLDGTFYLNHTFKKVSVTFDSSVSWPGNDRLLTPNEFEIKRSVDGE GYNVAQCNMTKDWFLIQMLANYNIGYQGFYIPESYKDRMYSFFRNFQPMSRQVVDETKYKDYQQVGII HQHNNSGFVGYLAPTMREGQAYPANFPYPLIGKTAVDSVTQKKFLCDRTLWRIPFSSNFMSMGALTDLG QNLLYANSAHALDMTFEVDPMDEPTLLYVLFEVFDVVRVHQPHRGVIETVYLRTPFSAGNATT Polynucleotide sequence encoding ChAd155 hexon SEQ ID NO: 6 ATGGCGACCCCATCGATGATGCCGCAGTGGTCGTACATGCACATCTCGGGCCAGGACGCCTCGGAGT ACCTGAGCCCCGGGCTGGTGCAGTTCGCCCGCGCCACCGAGAGCTACTTCAGCCTGAGTAACAAGTT TAGGAACCCCACGGTGGCGCCCACGCACGATGTGACCACCGACCGGTCTCAGCGCCTGACGCTGCGG TTCATTCCCGTGGACCGCGAGGACACCGCGTACTCGTACAAGGCGCGGTTCACCCTGGCCGTGGGCG ACAACCGCGTGCTGGACATGGCCTCCACCTACTTTGACATCCGCGGGGTGCTGGACCGGGGTCCCAC TTTCAAGCCCTACTCTGGCACCGCCTACAACTCCCTGGCCCCCAAGGGCGCTCCCAACTCCTGCGAGT GGGAGCAAGAGGAAACTCAGGCAGTTGAAGAAGCAGCAGAAGAGGAAGAAGAAGATGCTGACGGT CAAGCTGAGGAAGAGCAAGCAGCTACCAAAAAGACTCATGTATATGCTCAGGCTCCCCTTTCTGGCG AAAAAATTAGTAAAGATGGTCTGCAAATAGGAACGGACGCTACAGCTACAGAACAAAAACCTATTT ATGCAGACCCTACATTCCAGCCCGAACCCCAAATCGGGGAGTCCCAGTGGAATGAGGCAGATGCTAC AGTCGCCGGCGGTAGAGTGCTAAAGAAATCTACTCCCATGAAACCATGCTATGGTTCCTATGCAAGA CCCACAAATGCTAATGGAGGTCAGGGTGTACTAACGGCAAATGCCCAGGGACAGCTAGAATCTCAG GTTGAAATGCAATTCTTTTCAACTTCTGAAAACGCCCGTAACGAGGCTAACAACATTCAGCCCAAATT GGTGCTGTATAGTGAGGATGTGCACATGGAGACCCCGGATACGCACCTTTCTTACAAGCCCGCAAAA AGCGATGACAATTCAAAAATCATGCTGGGTCAGCAGTCCATGCCCAACAGACCTAATTACATCGGCT TCAGAGACAACTTTATCGGCCTCATGTATTACAATAGCACTGGCAACATGGGAGTGCTTGCAGGTCA GGCCTCTCAGTTGAATGCAGTGGTGGACTTGCAAGACAGAAACACAGAACTGTCCTACCAGCTCTTG CTTGATTCCATGGGTGACAGAACCAGATACTTTTCCATGTGGAATCAGGCAGTGGACAGTTATGACC CAGATGTTAGAATTATTGAAAATCATGGAACTGAAGACGAGCTCCCCAACTATTGTTTCCCTCTGGGT GGCATAGGGGTAACTGACACTTACCAGGCTGTTAAAACCAACAATGGCAATAACGGGGGCCAGGTG ACTTGGACAAAAGATGAAACTTTTGCAGATCGCAATGAAATAGGGGTGGGAAACAATTTCGCTATGG AGATCAACCTCAGTGCCAACCTGTGGAGAAACTTCCTGTACTCCAACGTGGCGCTGTACCTACCAGA CAAGCTTAAGTACAACCCCTCCAATGTGGACATCTCTGACAACCCCAACACCTACGATTACATGAAC AAGCGAGTGGTGGCCCCGGGGCTGGTGGACTGCTACATCAACCTGGGCGCGCGCTGGTCGCTGGACT ACATGGACAACGTCAACCCCTTCAACCACCACCGCAATGCGGGCCTGCGCTACCGCTCCATGCTCCT GGGCAACGGGCGCTACGTGCCCTTCCACATCCAGGTGCCCCAGAAGTTCTTTGCCATCAAGAACCTC CTCCTCCTGCCGGGCTCCTACACCTACGAGTGGAACTTCAGGAAGGATGTCAACATGGTCCTCCAGA GCTCTCTGGGTAACGATCTCAGGGTGGACGGGGCCAGCATCAAGTTCGAGAGCATCTGCCTCTACGC CACCTTCTTCCCCATGGCCCACAACACGGCCTCCACGCTCGAGGCCATGCTCAGGAACGACACCAAC GACCAGTCCTTCAATGACTACCTCTCCGCCGCCAACATGCTCTACCCCATACCCGCCAACGCCACCAA CGTCCCCATCTCCATCCCCTCGCGCAACTGGGCGGCCTTCCGCGGCTGGGCCTTCACCCGCCTCAAGA CCAAGGAGACCCCCTCCCTGGGCTCGGGATTCGACCCCTACTACACCTACTCGGGCTCCATTCCCTAC CTGGACGGCACCTTCTACCTCAACCACACTTTCAAGAAGGTCTCGGTCACCTTCGACTCCTCGGTCAG CTGGCCGGGCAACGACCGTCTGCTCACCCCCAACGAGTTCGAGATCAAGCGCTCGGTCGACGGGGAG GGCTACAACGTGGCCCAGTGCAACATGACCAAGGACTGGTTCCTGGTCCAGATGCTGGCCAACTACA ACATCGGCTACCAGGGCTTCTACATCCCAGAGAGCTACAAGGACAGGATGTACTCCTTCTTCAGGAA CTTCCAGCCCATGAGCCGGCAGGTGGTGGACCAGACCAAGTACAAGGACTACCAGGAGGTGGGCAT CATCCACCAGCACAACAACTCGGGCTTCGTGGGCTACCTCGCCCCCACCATGCGCGAGGGACAGGCC TACCCCGCCAACTTCCCCTATCCGCTCATAGGCAAGACCGCGGTCGACAGCATCACCCAGAAAAAGT TCCTCTGCGACCGCACCCTCTGGCGCATCCCCTTCTCCAGCAACTTCATGTCCATGGGTGCGCTCTCG GACCTGGGCCAGAACTTGCTCTACGCCAACTCCGCCCACGCCCTCGACATGACCTTCGAGGTCGACC CCATGGACGAGCCCACCCTTCTCTATGTTCTGTTCGAAGTCTTTGACGTGGTCCGGGTCCACCAGCCG CACCGCGGCGTCATCGAGACCGTGTACCTGCGTACGCCCTTCTCGGCCGGCAACGCCACCACC Polynucleotide sequence encoding ChAd155#1434 backbone construct SEQ ID NO: 7 CATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAATGAGATGGGCGGCGCGGGGCG GGGCGCGGGGCGGGAGGCGGGTTTGGGGGCGGGCCGGCGGGCGGGGCGGTGTGGCGGAAGTGGAC TTTGTAAGTGTGGCGGATGTGACTTGCTAGTGCCGGGCGCGGTAAAAGTGACGTTTTCCGTGCGCGA CAACGCCCCCGGGAAGTGACATTTTTCCCGCGGTTTTTACCGGATGTTGTAGTGAATTTGGGCGTAAC CAAGTAAGATTTGGCCATTTTCGCGGGAAAACTGAAACGGGGAAGTGAAATCTGATTAATTTTGCGT TAGTCATACCGCGTAATATTTGTCTAGGGCCGAGGGACTTTGGCCGATTACGTGGAGGACTCGCCCA GGTGTTTTTTGAGGTGAATTTCCGCGTTCCGGGTCAAAGTCTGCGTTTTATTATTATAGGATATCCCAT TGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTT GACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATG GAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGT GGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCT ATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCC TACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCA ATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAG TTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAA TGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCTCCCTATCAGTGATAGAGATCT CCCTATCAGTGATAGAGATCGTCGACGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCAT CCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGCGGCCGGGAACGGTGCA TTGGAACGCGGATTCCCCGTGCCAAGAGTGAGATCTTCCGTTTATCTAGGTACCGGGCCCCCCCTCGA GGTCGACGGTATCGATAAGCTTCACGCTGCCGCAAGCACTCAGGGCGCAAGGGCTGCTAAAGGAAG CGGAACACGTAGAAAGCCAGTCCGCAGAAACGGTGCTGACCCCGGATGAATGTCAGCTACTGGGCT ATCTGGACAAGGGAAAACGCAAGCGCAAAGAGAAAGCAGGTAGCTTGCAGTGGGCTTACATGGCGA TAGCTAGACTGGGCGGTTTTATGGACAGCAAGCGAACCGGAATTGCCAGCTGGGGCGCCCTCTGGTA AGGTTGGGAAGCCCTGCAAAGTAAACTGGATGGCTTTCTTGCCGCCAAGGATCTGATGGCGCAGGGG ATCAAGATCTAACCAGGAGCTATTTAATGGCAACAGTTAACCAGCTGGTACGCAAACCACGTGCTCG CAAAGTTGCGAAAAGCAACGTGCCTGCGCTGGAAGCATGCCCGCAAAAACGTGGCGTATGTACTCGT GTATATACTACCACTCCTAAAAAACCGAACTCCGCGCTGCGTAAAGTATGCCGTGTTCGTCTGACTAA CGGTTTCGAAGTGACTTCCTACATCGGTGGTGAAGGTCACAACCTGCAGGAGCACTCCGTGATCCTG ATCCGTGGCGGTCGTGTTAAAGACCTCCCGGGTGTTCGTTACCACACCGTACGTGGTGCGCTTGACTG CTCCGGCGTTAAAGACCGTAAGCAGGCTCGTTCCAAGTATGGCGTGAAGCGTCCTAAGGCTTAATGG TAGATCTGATCAAGAGACAGGATGACGGTCGTTTCGCATGCTTGAACAAGATGGATTGCACGCAGGT TCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTG ATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGT GCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCG CAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCA GGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGC TGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACG TACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCA GCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCG ATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTG GGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCG AATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTAT CGCCTTCTTGACGAGTTCTTCTGAGCGGGACTCTGGGGTTCGAAATGACCGACCAAGCGACGCCCAA CCTGCCATCACGAGATTTCGATTCCACCGCCGCCTTCTATGAAAGGTTGGGCTTCGGAATCGTTTTCC GGGACGCCGGCTGGATGATCCTCCAGCGCGGGGATCTCATGCTGGAGTTCTTCGCCCACCCCGGGCT CGATCCCCTCGGGGGGAATCAGAATTCAGTCGACAGCGGCCGCGATCTGCTGTGCCTTCTAGTTGCC AGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTT CCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGT GGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT CTATGGCCGATCAGCGATCGCTGAGGTGGGTGAGTGGGCGTGGCCTGGGGTGGTCATGAAAATATAT AAGTTGGGGGTCTTAGGGTCTCTTTATTTGTGTTGCAGAGACCGCCGGAGCCATGAGCGGGAGCAGC AGCAGCAGCAGTAGCAGCAGCGCCTTGGATGGCAGCATCGTGAGCCCTTATTTGACGACGCGGATGC CCCACTGGGCCGGGGTGCGTCAGAATGTGATGGGCTCCAGCATCGACGGCCGACCCGTCCTGCCCGC AAATTCCGCCACGCTGACCTATGCGACCGTCGCGGGGACGCCGTTGGACGCCACCGCCGCCGCCGCC GCCACCGCAGCCGCCTCGGCCGTGCGCAGCCTGGCCACGGACTTTGCATTCCTGGGACCACTGGCGA CAGGGGCTACTTCTCGGGCCGCTGCTGCCGCCGTTCGCGATGACAAGCTGACCGCCCTGCTGGCGCA GTTGGATGCGCTTACTCGGGAACTGGGTGACCTTTCTCAGCAGGTCATGGCCCTGCGCCAGCAGGTCT CCTCCCTGCAAGCTGGCGGGAATGCTTCTCCCACAAATGCCGTTTAAGATAAATAAAACCAGACTCT GTTTGGATTAAAGAAAAGTAGCAAGTGCATTGCTCTCTTTATTTCATAATTTTCCGCGCGCGATAGGC CCTAGACCAGCGTTCTCGGTCGTTGAGGGTGCGGTGTATCTTCTCCAGGACGTGGTAGAGGTGGCTCT GGACGTTGAGATACATGGGCATGAGCCCGTCCCGGGGGTGGAGGTAGCACCACTGCAGAGCTTCATG CTCCGGGGTGGTGTTGTAGATGATCCAGTCGTAGCAGGAGCGCTGGGCATGGTGCCTAAAAATGTCC TTCAGCAGCAGGCCGATGGCCAGGGGGAGGCCCTTGGTGTAAGTGTTTACAAAACGGTTAAGTTGGG AAGGGTGCATTCGGGGAGAGATGATGTGCATCTTGGACTGTATTTTTAGATTGGCGATGTTTCCGCCC AGATCCCTTCTGGGATTCATGTTGTGCAGGACCACCAGTACAGTGTATCCGGTGCACTTGGGGAATTT GTCATGCAGCTTAGAGGGAAAAGCGTGGAAGAACTTGGAGACGCCTTTGTGGCCTCCCAGATTTTCC ATGCATTCGTCCATGATGATGGCAATGGGCCCGCGGGAGGCAGCTTGGGCAAAGATATTTCTGGGGT CGCTGACGTCGTAGTTGTGTTCCAGGGTGAGGTCGTCATAGGCCATTTTTACAAAGCGCGGGCGGAG GGTGCCCGACTGGGGGATGATGGTCCCCTCTGGCCCTGGGGCGTAGTTGCCCTCGCAGATCTGCATTT CCCAGGCCTTAATCTCGGAGGGGGGAATCATATCCACCTGCGGGGCGATGAAGAAAACGGTTTCCGG AGCCGGGGAGATTAACTGGGATGAGAGCAGGTTTCTAAGCAGCTGTGATTTTCCACAACCGGTGGGC CCATAAATAACACCTATAACCGGTTGCAGCTGGTAGTTTAGAGAGCTGCAGCTGCCGTCGTCCCGGA GGAGGGGGGCCACCTCGTTGAGCATGTCCCTGACGCGCATGTTCTCCCCGACCAGATCCGCCAGAAG GCGCTCGCCGCCCAGGGACAGCAGCTCTTGCAAGGAAGCAAAGTTTTTCAGCGGCTTGAGGCCGTCC GCCGTGGGCATGTTTTTCAGGGTCTGGCTCAGCAGCTCCAGGCGGTCCCAGAGCTCGGTGACGTGCT CTACGGCATCTCTATCCAGCATATCTCCTCGTTTCGCGGGTTGGGGCGACTTTCGCTGTAGGGCACCA AGCGGTGGTCGTCCAGCGGGGCCAGAGTCATGTCCTTCCATGGGCGCAGGGTCCTCGTCAGGGTGGT CTGGGTCACGGTGAAGGGGTGCGCTCCGGGCTGAGCGCTTGCCAAGGTGCGCTTGAGGCTGGTTCTG CTGGTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGCGTCGGCCAGGTAGCATTTGACCATGGTGTCATA GTCCAGCCCCTCCGCGGCGTGTCCCTTGGCGCGCAGCTTGCCCTTGGAGGTGGCGCCGCACGAGGGG CAGAGCAGGCTCTTGAGCGCGTAGAGCTTGGGGGCGAGGAAGACCGATTCGGGGGAGTAGGCGTCC GCGCCGCAGACCCCGCACACGGTCTCGCACTCCACCAGCCAGGTGAGCTCGGGGCGCGCCGGGTCAA AAACCAGGTTTCCCCCATGCTTTTTGATGCGTTTCTTACCTCGGGTCTCCATGAGGTGGTGTCCCCGCT CGGTGACGAAGAGGCTGTCCGTGTCTCCGTAGACCGACTTGAGGGGTCTTTTCTCCAGGGGGGTCCC TCGGTCTTCCTCGTAGAGGAACTCGGACCACTCTGAGACGAAGGCCCGCGTCCAGGCCAGGACGAAG GAGGCTATGTGGGAGGGGTAGCGGTCGTTGTCCACTAGGGGGTCCACCTTCTCCAAGGTGTGAAGAC ACATGTCGCCTTCCTCGGCGTCCAGGAAGGTGATTGGCTTGTAGGTGTAGGCCACGTGACCGGGGGT TCCTGACGGGGGGGTATAAAAGGGGGTGGGGGCGCGCTCGTCGTCACTCTCTTCCGCATCGCTGTCT GCGAGGGCCAGCTGCTGGGGTGAGTATTCCCTCTCGAAGGCGGGCATGACCTCCGCGCTGAGGTTGT CAGTTTCCAAAAACGAGGAGGATTTGATGTTCACCTGTCCCGAGGTGATACCTTTGAGGGTACCCGC GTCCATCTGGTCAGAAAACACGATCTTTTTATTGTCCAGCTTGGTGGCGAACGACCCGTAGAGGGCG TTGGAGAGCAGCTTGGCGATGGAGCGCAGGGTCTGGTTCTTGTCCCTGTCGGCGCGCTCCTTGGCCGC GATGTTGAGCTGCACGTACTCGCGCGCGACGCAGCGCCACTCGGGGAAGACGGTGGTGCGCTCGTCG GGCACCAGGCGCACGCGCCAGCCGCGGTTGTGCAGGGTGACCAGGTCCACGCTGGTGGCGACCTCGC CGCGCAGGCGCTCGTTGGTCCAGCAGAGACGGCCGCCCTTGCGCGAGCAGAAGGGGGGCAGGGGGT CGAGCTGGGTCTCGTCCGGGGGGTCCGCGTCCACGGTGAAAACCCCGGGGCGCAGGCGCGCGTCGA AGTAGTCTATCTTGCAACCTTGCATGTCCAGCGCCTGCTGCCAGTCGCGGGCGGCGAGCGCGCGCTC GTAGGGGTTGAGCGGCGGGCCCCAGGGCATGGGGTGGGTGAGTGCGGAGGCGTACATGCCGCAGAT GTCATAGACGTAGAGGGGCTCCCGCAGGACCCCGATGTAGGTGGGGTAGCAGCGGCCGCCGCGGAT GCTGGCGCGCACGTAGTCATACAGCTCGTGCGAGGGGGCGAGGAGGTCGGGGCCCAGGTTGGTGCG GGCGGGGCGCTCCGCGCGGAAGACGATCTGCCTGAAGATGGCATGCGAGTTGGAAGAGATGGTGGG GCGCTGGAAGACGTTGAAGCTGGCGTCCTGCAGGCCGACGGCGTCGCGCACGAAGGAGGCGTAGGA GTCGCGCAGCTTGTGTACCAGCTCGGCGGTGACCTGCACGTCGAGCGCGCAGTAGTCGAGGGTCTCG CGGATGATGTCATATTTAGCCTGCCCCTTCTTTTTCCACAGCTCGCGGTTGAGGACAAACTCTTCGCG GTCTTTCCAGTACTCTTGGATCGGGAAACCGTCCGGTTCCGAACGGTAAGAGCCTAGCATGTAGAAC TGGTTGACGGCCTGGTAGGCGCAGCAGCCCTTCTCCACGGGGAGGGCGTAGGCCTGCGCGGCCTTGC GGAGCGAGGTGTGGGTCAGGGCGAAGGTGTCCCTGACCATGACTTTGAGGTACTGGTGCTTGAAGTC GGAGTCGTCGCAGCCGCCCCGCTCCCAGAGCGAGAAGTCGGTGCGCTTCTTGGAGCGGGGGTTGGGC AGAGCGAAGGTGACATCGTTGAAGAGGATTTTGCCCGCGCGGGGCATGAAGTTGCGGGTGATGCGG AAGGGCCCCGGCACTTCAGAGCGGTTGTTGATGACCTGGGCGGCGAGCACGATCTCGTCGAAGCCGT TGATGTTGTGGCCCACGATGTAGAGTTCCAGGAAGCGGGGCCGGCCCTTTACGGTGGGCAGCTTCTT TAGCTCTTCGTAGGTGAGCTCCTCGGGCGAGGCGAGGCCGTGCTCGGCCAGGGCCCAGTCCGCGAGG TGCGGGTTGTCTCTGAGGAAGGACTTCCAGAGGTCGCGGGCCAGGAGGGTCTGCAGGCGGTCTCTGA AGGTCCTGAACTGGCGGCCCACGGCCATTTTTTCGGGGGTGATGCAGTAGAAGGTGAGGGGGTCTTG CTGCCAGCGGTCCCAGTCGAGCTGCAGGGCGAGGTCGCGCGCGGCGGTGACCAGGCGCTCGTCGCCC CCGAATTTCATGACCAGCATGAAGGGCACGAGCTGCTTTCCGAAGGCCCCCATCCAAGTGTAGGTCT CTACATCGTAGGTGACAAAGAGGCGCTCCGTGCGAGGATGCGAGCCGATCGGGAAGAACTGGATCT CCCGCCACCAGTTGGAGGAGTGGCTGTTGATGTGGTGGAAGTAGAAGTCCCGTCGCCGGGCCGAACA CTCGTGCTGGCTTTTGTAAAAGCGAGCGCAGTACTGGCAGCGCTGCACGGGCTGTACCTCATGCACG AGATGCACCTTTCGCCCGCGCACGAGGAAGCCGAGGGGAAATCTGAGCCCCCCGCCTGGCTCGCGGC ATGGCTGGTTCTCTTCTACTTTGGATGCGTGTCCGTCTCCGTCTGGCTCCTCGAGGGGTGTTACGGTG GAGCGGACCACCACGCCGCGCGAGCCGCAGGTCCAGATATCGGCGCGCGGCGGTCGGAGTTTGATG ACGACATCGCGCAGCTGGGAGCTGTCCATGGTCTGGAGCTCCCGCGGCGGCGGCAGGTCAGCCGGG AGTTCTTGCAGGTTCACCTCGCAGAGTCGGGCCAGGGCGCGGGGCAGGTCTAGGTGGTACCTGATCT CTAGGGGCGTGTTGGTGGCGGCGTCGATGGCTTGCAGGAGCCCGCAGCCCCGGGGGGCGACGACGG TGCCCCGCGGGGTGGTGGTGGTGGTGGCGGTGCAGCTCAGAAGCGGTGCCGCGGGCGGGCCCCCGG AGGTAGGGGGGGCTCCGGTCCCGCGGGCAGGGGCGGCAGCGGCACGTCGGCGTGGAGCGCGGGCAG GAGTTGGTGCTGTGCCCGGAGGTTGCTGGCGAAGGCGACGACGCGGCGGTTGATCTCCTGGATCTGG CGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCTTGAACCTGAAAGAGAGTTCGACAGAATCAATCT CGGTGTCATTGACCGCGGCCTGGCGCAGGATCTCCTGCACGTCTCCCGAGTTGTCTTGGTAGGCGATC TCGGCCATGAACTGCTCGATCTCTTCCTCCTGGAGGTCTCCGCGTCCGGCGCGTTCCACGGTGGCCGC CAGGTCGTTGGAGATGCGCCCCATGAGCTGCGAGAAGGCGTTGAGTCCGCCCTCGTTCCAGACTCGG CTGTAGACCACGCCCCCCTGGTCATCGCGGGCGCGCATGACCACCTGCGCGAGGTTGAGCTCCACGT GCCGCGCGAAGACGGCGTAGTTGCGCAGACGCTGGAAGAGGTAGTTGAGGGTGGTGGCGGTGTGCT CGGCCACGAAGAAGTTCATGACCCAGCGGCGCAACGTGGATTCGTTGATGTCCCCCAAGGCCTCCAG CCGTTCCATGGCCTCGTAGAAGTCCACGGCGAAGTTGAAAAACTGGGAGTTGCGCGCCGACACGGTC AACTCCTCCTCCAGAAGACGGATGAGCTCGGCGACGGTGTCGCGCACCTCGCGCTCGAAGGCTATGG GGATCTCTTCCTCCGCTAGCATCACCACCTCCTCCTCTTCCTCCTCTTCTGGCACTTCCATGATGGCTT CCTCCTCTTCGGGGGGTGGCGGCGGCGGCGGTGGGGGAGGGGGCGCTCTGCGCCGGCGGCGGCGCA CCGGGAGGCGGTCCACGAAGCGCGCGATCATCTCCCCGCGGCGGCGGCGCATGGTCTCGGTGACGGC GCGGCCGTTCTCCCGGGGGCGCAGTTGGAAGACGCCGCCGGACATCTGGTGCTGGGGCGGGTGGCCG TGAGGCAGCGAGACGGCGCTGACGATGCATCTCAACAATTGCTGCGTAGGTACGCCGCCGAGGGAC CTGAGGGAGTCCATATCCACCGGATCCGAAAACCTTTCGAGGAAGGCGTCTAACCAGTCGCAGTCGC AAGGTAGGCTGAGCACCGTGGCGGGCGGCGGGGGGTGGGGGGAGTGTCTGGCGGAGGTGCTGCTGA TGATGTAATTGAAGTAGGCGGACTTGACACGGCGGATGGTCGACAGGAGCACCATGTCCTTGGGTCC GGCCTGCTGGATGCGGAGGCGGTCGGCTATGCCCCAGGCTTCGTTCTGGCATCGGCGCAGGTCCTTG TAGTAGTCTTGCATGAGCCTTTCCACCGGCACCTCTTCTCCTTCCTCTTCTGCTTCTTCCATGTCTGCTT CGGCCCTGGGGCGGCGCCGCGCCCCCCTGCCCCCCATGCGCGTGACCCCGAACCCCCTGAGCGGTTG GAGCAGGGCCAGGTCGGCGACGACGCGCTCGGCCAGGATGGCCTGCTGCACCTGCGTGAGGGTGGT TTGGAAGTCATCCAAGTCCACGAAGCGGTGGTAGGCGCCCGTGTTGATGGTGTAGGTGCAGTTGGCC ATGACGGACCAGTTGACGGTCTGGTGGCCCGGTTGCGACATCTCGGTGTACCTGAGTCGCGAGTAGG CGCGGGAGTCGAAGACGTAGTCGTTGCAAGTCCGCACCAGGTACTGGTAGCCCACCAGGAAGTGCG GCGGCGGCTGGCGGTAGAGGGGCCAGCGCAGGGTGGCGGGGGCTCCGGGGGCCAGGTCTTCCAGCA TGAGGCGGTGGTAGGCGTAGATGTACCTGGACATCCAGGTGATACCCGCGGCGGTGGTGGAGGCGC GCGGGAAGTCGCGCACCCGGTTCCAGATGTTGCGCAGGGGCAGAAAGTGCTCCATGGTAGGCGTGCT CTGTCCAGTCAGACGCGCGCAGTCGTTGATACTCTAGACCAGGGAAAACGAAAGCCGGTCAGCGGG CACTCTTCCGTGGTCTGGTGAATAGATCGCAAGGGTATCATGGCGGAGGGCCTCGGTTCGAGCCCCG GGTCCGGGCCGGACGGTCCGCCATGATCCACGCGGTTACCGCCCGCGTGTCGAACCCAGGTGTGCGA CGTCAGACAACGGTGGAGTGTTCCTTTTGGCGTTTTTCTGGCCGGGCGCCGGCGCCGCGTAAGAGAC TAAGCCGCGAAAGCGAAAGCAGTAAGTGGCTCGCTCCCCGTAGCCGGAGGGATCCTTGCTAAGGGTT GCGTTGCGGCGAACCCCGGTTCGAATCCCGTACTCGGGCCGGCCGGACCCGCGGCTAAGGTGTTGGA TTGGCCTCCCCCTCGTATAAAGACCCCGCTTGCGGATTGACTCCGGACACGGGGACGAGCCCCTTTTA TTTTTGCTTTCCCCAGATGCATCCGGTGCTGCGGCAGATGCGCCCCCCGCCCCAGCAGCAGCAACAAC ACCAGCAAGAGCGGCAGCAACAGCAGCGGGAGTCATGCAGGGCCCCCTCACCCACCCTCGGCGGGC CGGCCACCTCGGCGTCCGCGGCCGTGTCTGGCGCCTGCGGCGGCGGCGGGGGGCCGGCTGACGACCC CGAGGAGCCCCCGCGGCGCAGGGCCAGACACTACCTGGACCTGGAGGAGGGCGAGGGCCTGGCGCG GCTGGGGGCGCCGTCTCCCGAGCGCCACCCGCGGGTGCAGCTGAAGCGCGACTCGCGCGAGGCGTA CGTGCCTCGGCAGAACCTGTTCAGGGACCGCGCGGGCGAGGAGCCCGAGGAGATGCGGGACAGGAG GTTCAGCGCAGGGCGGGAGCTGCGGCAGGGGCTGAACCGCGAGCGGCTGCTGCGCGAGGAGGACTT TGAGCCCGACGCGCGGACGGGGATCAGCCCCGCGCGCGCGCACGTGGCGGCCGCCGACCTGGTGAC GGCGTACGAGCAGACGGTGAACCAGGAGATCAACTTCCAAAAGAGTTTCAACAACCACGTGCGCAC GCTGGTGGCGCGCGAGGAGGTGACCATCGGGCTGATGCACCTGTGGGACTTTGTAAGCGCGCTGGTG CAGAACCCCAACAGCAAGCCTCTGACGGCGCAGCTGTTCCTGATAGTGCAGCACAGCAGGGACAAC GAGGCGTTTAGGGACGCGCTGCTGAACATCACCGAGCCCGAGGGTCGGTGGCTGCTGGACCTGATTA ACATCCTGCAGAGCATAGTGGTGCAGGAGCGCAGCCTGAGCCTGGCCGACAAGGTGGCGGCCATCA ACTACTCGATGCTGAGCCTGGGCAAGTTTTACGCGCGCAAGATCTACCAGACGCCGTACGTGCCCAT AGACAAGGAGGTGAAGATCGACGGTTTTTACATGCGCATGGCGCTGAAGGTGCTCACCCTGAGCGAC GACCTGGGCGTGTACCGCAACGAGCGCATCCACAAGGCCGTGAGCGTGAGCCGGCGGCGCGAGCTG AGCGACCGCGAGCTGATGCACAGCCTGCAGCGGGCGCTGGCGGGCGCCGGCAGCGGCGACAGGGAG GCGGAGTCCTACTTCGATGCGGGGGCGGACCTGCGCTGGGCGCCCAGCCGGCGGGCCCTGGAGGCC GCGGGGGTCCGCGAGGACTATGACGAGGACGGCGAGGAGGATGAGGAGTACGAGCTAGAGGAGGG CGAGTACCTGGACTAAACCGCGGGTGGTGTTTCCGGTAGATGCAAGACCCGAACGTGGTGGACCCGG CGCTGCGGGCGGCTCTGCAGAGCCAGCCGTCCGGCCTTAACTCCTCAGACGACTGGCGACAGGTCAT GGACCGCATCATGTCGCTGACGGCGCGTAACCCGGACGCGTTCCGGCAGCAGCCGCAGGCCAACAG GCTCTCCGCCATCCTGGAGGCGGTGGTGCCTGCGCGCTCGAACCCCACGCACGAGAAGGTGCTGGCC ATAGTGAACGCGCTGGCCGAGAACAGGGCCATCCGCCCGGACGAGGCCGGGCTGGTGTACGACGCG CTGCTGCAGCGCGTGGCCCGCTACAACAGCGGCAACGTGCAGACCAACCTGGACCGGCTGGTGGGG GACGTGCGCGAGGCGGTGGCGCAGCGCGAGCGCGCGGATCGGCAGGGCAACCTGGGCTCCATGGTG GCGCTGAATGCCTTCCTGAGCACGCAGCCGGCCAACGTGCCGCGGGGGCAGGAAGACTACACCAAC TTTGTGAGCGCGCTGCGGCTGATGGTGACCGAGACCCCCCAGAGCGAGGTGTACCAGTCGGGCCCGG ACTACTTCTTCCAGACCAGCAGACAGGGCCTGCAGACGGTGAACCTGAGCCAGGCTTTCAAGAACCT GCGGGGGCTGTGGGGCGTGAAGGCGCCCACCGGCGACCGGGCGACGGTGTCCAGCCTGCTGACGCC CAACTCGCGCCTGCTGCTGCTGCTGATCGCGCCGTTCACGGACAGCGGCAGCGTGTCCCGGGACACC TACCTGGGGCACCTGCTGACCCTGTACCGCGAGGCCATCGGGCAGGCGCAGGTGGACGAGCACACCT TCCAGGAGATCACCAGCGTGAGCCGCGCGCTGGGGCAGGAGGACACGAGCAGCCTGGAGGCGACTC TGAACTACCTGCTGACCAACCGGCGGCAGAAGATTCCCTCGCTGCACAGCCTGACCTCCGAGGAGGA GCGCATCTTGCGCTACGTGCAGCAGAGCGTGAGCCTGAACCTGATGCGCGACGGGGTGACGCCCAGC GTGGCGCTGGACATGACCGCGCGCAACATGGAACCGGGCATGTACGCCGCGCACCGGCCTTACATCA ACCGCCTGATGGACTACCTGCATCGCGCGGCGGCCGTGAACCCCGAGTACTTTACCAACGCCATCCT GAACCCGCACTGGCTCCCGCCGCCCGGGTTCTACAGCGGGGGCTTCGAGGTCCCGGAGACCAACGAT GGCTTCCTGTGGGACGACATGGACGACAGCGTGTTCTCCCCGCGGCCGCAGGCGCTGGCGGAAGCGT CCCTGCTGCGTCCCAAGAAGGAGGAGGAGGAGGAGGCGAGTCGCCGCCGCGGCAGCAGCGGCGTGG CTTCTCTGTCCGAGCTGGGGGCGGCAGCCGCCGCGCGCCCCGGGTCCCTGGGCGGCAGCCCCTTTCC GAGCCTGGTGGGGTCTCTGCACAGCGAGCGCACCACCCGCCCTCGGCTGCTGGGCGAGGACGAGTAC CTGAATAACTCCCTGCTGCAGCCGGTGCGGGAGAAAAACCTGCCTCCCGCCTTCCCCAACAACGGGA TAGAGAGCCTGGTGGACAAGATGAGCAGATGGAAGACCTATGCGCAGGAGCACAGGGACGCGCCTG CGCTCCGGCCGCCCACGCGGCGCCAGCGCCACGACCGGCAGCGGGGGCTGGTGTGGGATGACGAGG ACTCCGCGGACGATAGCAGCGTGCTGGACCTGGGAGGGAGCGGCAACCCGTTCGCGCACCTGCGCCC CCGCCTGGGGAGGATGTTTTAAAAAAAAAAAAAAAAAGCAAGAAGCATGATGCAAAAATTAAATAA AACTCACCAAGGCCATGGCGACCGAGCGTTGGTTTCTTGTGTTCCCTTCAGTATGCGGCGCGCGGCG ATGTACCAGGAGGGACCTCCTCCCTCTTACGAGAGCGTGGTGGGCGCGGCGGCGGCGGCGCCCTCTT CTCCCTTTGCGTCGCAGCTGCTGGAGCCGCCGTACGTGCCTCCGCGCTACCTGCGGCCTACGGGGGG GAGAAACAGCATCCGTTACTCGGAGCTGGCGCCCCTGTTCGACACCACCCGGGTGTACCTGGTGGAC AACAAGTCGGCGGACGTGGCCTCCCTGAACTACCAGAACGACCACAGCAATTTTTTGACCACGGTCA TCCAGAACAATGACTACAGCCCGAGCGAGGCCAGCACCCAGACCATCAATCTGGATGACCGGTCGC ACTGGGGCGGCGACCTGAAAACCATCCTGCACACCAACATGCCCAACGTGAACGAGTTCATGTTCAC CAATAAGTTCAAGGCGCGGGTGATGGTGTCGCGCTCGCACACCAAGGAAGACCGGGTGGAGCTGAA GTACGAGTGGGTGGAGTTCGAGCTGCCAGAGGGCAACTACTCCGAGACCATGACCATTGACCTGATG AACAACGCGATCGTGGAGCACTATCTGAAAGTGGGCAGGCAGAACGGGGTCCTGGAGAGCGACATC GGGGTCAAGTTCGACACCAGGAACTTCCGCCTGGGGCTGGACCCCGTGACCGGGCTGGTTATGCCCG GGGTGTACACCAACGAGGCCTTCCATCCCGACATCATCCTGCTGCCCGGCTGCGGGGTGGACTTCAC TTACAGCCGCCTGAGCAACCTCCTGGGCATCCGCAAGCGGCAGCCCTTCCAGGAGGGCTTCAGGATC ACCTACGAGGACCTGGAGGGGGGCAACATCCCCGCGCTCCTCGATGTGGAGGCCTACCAGGATAGCT TGAAGGAAAATGAGGCGGGACAGGAGGATACCGCCCCCGCCGCCTCCGCCGCCGCCGAGCAGGGCG AGGATGCTGCTGACACCGCGGCCGCGGACGGGGCAGAGGCCGACCCCGCTATGGTGGTGGAGGCTC CCGAGCAGGAGGAGGACATGAATGACAGTGCGGTGCGCGGAGACACCTTCGTCACCCGGGGGGAGG AAAAGCAAGCGGAGGCCGAGGCCGCGGCCGAGGAAAAGCAACTGGCGGCAGCAGCGGCGGCGGCG GCGTTGGCCGCGGCGGAGGCTGAGTCTGAGGGGACCAAGCCCGCCAAGGAGCCCGTGATTAAGCCC CTGACCGAAGATAGCAAGAAGCGCAGTTACAACCTGCTCAAGGACAGCACCAACACCGCGTACCGC AGCTGGTACCTGGCCTACAACTACGGCGACCCGTCGACGGGGGTGCGCTCCTGGACCCTGCTGTGCA CGCCGGACGTGACCTGCGGCTCGGAGCAGGTGTACTGGTCGCTGCCCGACATGATGCAAGACCCCGT GACCTTCCGCTCCACGCGGCAGGTCAGCAACTTCCCGGTGGTGGGCGCCGAGCTGCTGCCCGTGCAC TCCAAGAGCTTCTACAACGACCAGGCCGTCTACTCCCAGCTCATCCGCCAGTTCACCTCTCTGACCCA CGTGTTCAATCGCTTTCCTGAGAACCAGATTCTGGCGCGCCCGCCCGCCCCCACCATCACCACCGTCA GTGAAAACGTTCCTGCTCTCACAGATCACGGGACGCTACCGCTGCGCAACAGCATCGGAGGAGTCCA GCGAGTGACCGTTACTGACGCCAGACGCCGCACCTGCCCCTACGTTTACAAGGCCTTGGGCATAGTC TCGCCGCGCGTCCTTTCCAGCCGCACTTTTTGAGCAACACCACCATCATGTCCATCCTGATCTCACCC AGCAATAACTCCGGCTGGGGACTGCTGCGCGCGCCCAGCAAGATGTTCGGAGGGGCGAGGAAGCGT TCCGAGCAGCACCCCGTGCGCGTGCGCGGGCACTTCCGCGCCCCCTGGGGAGCGCACAAACGCGGCC GCGCGGGGCGCACCACCGTGGACGACGCCATCGACTCGGTGGTGGAGCAGGCGCGCAACTACAGGC CCGCGGTCTCTACCGTGGACGCGGCCATCCAGACCGTGGTGCGGGGCGCGCGGCGGTACGCCAAGCT GAAGAGCCGCCGGAAGCGCGTGGCCCGCCGCCACCGCCGCCGACCCGGGGCCGCCGCCAAACGCGC CGCCGCGGCCCTGCTTCGCCGGGCCAAGCGCACGGGCCGCCGCGCCGCCATGAGGGCCGCGCGCCGC TTGGCCGCCGGCATCACCGCCGCCACCATGGCCCCCCGTACCCGAAGACGCGCGGCCGCCGCCGCCG CCGCCGCCATCAGTGACATGGCCAGCAGGCGCCGGGGCAACGTGTACTGGGTGCGCGACTCGGTGAC CGGCACGCGCGTGCCCGTGCGCTTCCGCCCCCCGCGGACTTGAGATGATGTGAAAAAACAACACTGA GTCTCCTGCTGTTGTGTGTATCCCAGCGGCGGCGGCGCGCGCAGCGTCATGTCCAAGCGCAAAATCA AAGAAGAGATGCTCCAGGTCGTCGCGCCGGAGATCTATGGGCCCCCGAAGAAGGAAGAGCAGGATT CGAAGCCCCGCAAGATAAAGCGGGTCAAAAAGAAAAAGAAAGATGATGACGATGCCGATGGGGAG GTGGAGTTCCTGCGCGCCACGGCGCCCAGGCGCCCGGTGCAGTGGAAGGGCCGGCGCGTAAAGCGC GTCCTGCGCCCCGGCACCGCGGTGGTCTTCACGCCCGGCGAGCGCTCCACCCGGACTTTCAAGCGCG TCTATGACGAGGTGTACGGCGACGAAGACCTGCTGGAGCAGGCCAACGAGCGCTTCGGAGAGTTTGC TTACGGGAAGCGTCAGCGGGCGCTGGGGAAGGAGGACCTGCTGGCGCTGCCGCTGGACCAGGGCAA CCCCACCCCCAGTCTGAAGCCCGTGACCCTGCAGCAGGTGCTGCCGAGCAGCGCACCCTCCGAGGCG AAGCGGGGTCTGAAGCGCGAGGGCGGCGACCTGGCGCCCACCGTGCAGCTCATGGTGCCCAAGCGG CAGAGGCTGGAGGATGTGCTGGAGAAAATGAAAGTAGACCCCGGTCTGCAGCCGGACATCAGGGTC CGCCCCATCAAGCAGGTGGCGCCGGGCCTCGGCGTGCAGACCGTGGACGTGGTCATCCCCACCGGCA ACTCCCCCGCCGCCGCCACCACTACCGCTGCCTCCACGGACATGGAGACACAGACCGATCCCGCCGC AGCCGCAGCCGCAGCCGCCGCCGCGACCTCCTCGGCGGAGGTGCAGACGGACCCCTGGCTGCCGCCG GCGATGTCAGCTCCCCGCGCGCGTCGCGGGCGCAGGAAGTACGGCGCCGCCAACGCGCTCCTGCCCG AGTACGCCTTGCATCCTTCCATCGCGCCCACCCCCGGCTACCGAGGCTATACCTACCGCCCGCGAAG AGCCAAGGGTTCCACCCGCCGTCCCCGCCGACGCGCCGCCGCCACCACCCGCCGCCGCCGCCGCAGA CGCCAGCCCGCACTGGCTCCAGTCTCCGTGAGGAAAGTGGCGCGCGACGGACACACCCTGGTGCTGC CCAGGGCGCGCTACCACCCCAGCATCGTTTAAAAGCCTGTTGTGGTTCTTGCAGATATGGCCCTCACT TGCCGCCTCCGTTTCCCGGTGCCGGGATACCGAGGAGGAAGATCGCGCCGCAGGAGGGGTCTGGCCG GCCGCGGCCTGAGCGGAGGCAGCCGCCGCGCGCACCGGCGGCGACGCGCCACCAGCCGACGCATGC GCGGCGGGGTGCTGCCCCTGTTAATCCCCCTGATCGCCGCGGCGATCGGCGCCGTGCCCGGGATCGC CTCCGTGGCCTTGCAAGCGTCCCAGAGGCATTGACAGACTTGCAAACTTGCAAATATGGAAAAAAAA ACCCCAATAAAAAAGTCTAGACTCTCACGCTCGCTTGGTCCTGTGACTATTTTGTAGAATGGAAGAC ATCAACTTTGCGTCGCTGGCCCCGCGTCACGGCTCGCGCCCGTTCCTGGGACACTGGAACGATATCG GCACCAGCAACATGAGCGGTGGCGCCTTCAGTTGGGGCTCTCTGTGGAGCGGCATTAAAAGTATCGG GTCTGCCGTTAAAAATTACGGCTCCCGGGCCTGGAACAGCAGCACGGGCCAGATGTTGAGAGACAA GTTGAAAGAGCAGAACTTCCAGCAGAAGGTGGTGGAGGGCCTGGCCTCCGGCATCAACGGGGTGGT GGACCTGGCCAACCAGGCCGTGCAGAATAAGATCAACAGCAGACTGGACCCCCGGCCGCCGGTGGA GGAGGTGCCGCCGGCGCTGGAGACGGTGTCCCCCGATGGGCGTGGCGAGAAGCGCCCGCGGCCCGA TAGGGAAGAGACCACTCTGGTCACGCAGACCGATGAGCCGCCCCCGTATGAGGAGGCCCTGAAGCA AGGTCTGCCCACCACGCGGCCCATCGCGCCCATGGCCACCGGGGTGGTGGGCCGCCACACCCCCGCC ACGCTGGACTTGCCTCCGCCCGCCGATGTGCCGCAGCAGCAGAAGGCGGCACAGCCGGGCCCGCCCG CGACCGCCTCCCGTTCCTCCGCCGGTCCTCTGCGCCGCGCGGCCAGCGGCCCCCGCGGGGGGGTCGC GAGGCACGGCAACTGGCAGAGCACGCTGAACAGCATCGTGGGTCTGGGGGTGCGGTCCGTGAAGCG CCGCCGATGCTACTGAATAGCTTAGCTAACGTGTTGTATGTGTGTATGCGCCCTATGTCGCCGCCAGA GGAGCTGCTGAGTCGCCGCCGTTCGCGCGCCCACCACCACCGCCACTCCGCCCCTCAAGATGGCGAC CCCATCGATGATGCCGCAGTGGTCGTACATGCACATCTCGGGCCAGGACGCCTCGGAGTACCTGAGC CCCGGGCTGGTGCAGTTCGCCCGCGCCACCGAGAGCTACTTCAGCCTGAGTAACAAGTTTAGGAACC CCACGGTGGCGCCCACGCACGATGTGACCACCGACCGGTCTCAGCGCCTGACGCTGCGGTTCATTCC CGTGGACCGCGAGGACACCGCGTACTCGTACAAGGCGCGGTTCACCCTGGCCGTGGGCGACAACCGC GTGCTGGACATGGCCTCCACCTACTTTGACATCCGCGGGGTGCTGGACCGGGGTCCCACTTTCAAGCC CTACTCTGGCACCGCCTACAACTCCCTGGCCCCCAAGGGCGCTCCCAACTCCTGCGAGTGGGAGCAA GAGGAAACTCAGGCAGTTGAAGAAGCAGCAGAAGAGGAAGAAGAAGATGCTGACGGTCAAGCTGA GGAAGAGCAAGCAGCTACCAAAAAGACTCATGTATATGCTCAGGCTCCCCTTTCTGGCGAAAAAATT AGTAAAGATGGTCTGCAAATAGGAACGGACGCTACAGCTACAGAACAAAAACCTATTTATGCAGAC CCTACATTCCAGCCCGAACCCCAAATCGGGGAGTCCCAGTGGAATGAGGCAGATGCTACAGTCGCCG GCGGTAGAGTGCTAAAGAAATCTACTCCCATGAAACCATGCTATGGTTCCTATGCAAGACCCACAAA TGCTAATGGAGGTCAGGGTGTACTAACGGCAAATGCCCAGGGACAGCTAGAATCTCAGGTTGAAATG CAATTCTTTTCAACTTCTGAAAACGCCCGTAACGAGGCTAACAACATTCAGCCCAAATTGGTGCTGTA TAGTGAGGATGTGCACATGGAGACCCCGGATACGCACCTTTCTTACAAGCCCGCAAAAAGCGATGAC AATTCAAAAATCATGCTGGGTCAGCAGTCCATGCCCAACAGACCTAATTACATCGGCTTCAGAGACA ACTTTATCGGCCTCATGTATTACAATAGCACTGGCAACATGGGAGTGCTTGCAGGTCAGGCCTCTCAG TTGAATGCAGTGGTGGACTTGCAAGACAGAAACACAGAACTGTCCTACCAGCTCTTGCTTGATTCCA TGGGTGACAGAACCAGATACTTTTCCATGTGGAATCAGGCAGTGGACAGTTATGACCCAGATGTTAG AATTATTGAAAATCATGGAACTGAAGACGAGCTCCCCAACTATTGTTTCCCTCTGGGTGGCATAGGG GTAACTGACACTTACCAGGCTGTTAAAACCAACAATGGCAATAACGGGGGCCAGGTGACTTGGACA AAAGATGAAACTTTTGCAGATCGCAATGAAATAGGGGTGGGAAACAATTTCGCTATGGAGATCAACC TCAGTGCCAACCTGTGGAGAAACTTCCTGTACTCCAACGTGGCGCTGTACCTACCAGACAAGCTTAA GTACAACCCCTCCAATGTGGACATCTCTGACAACCCCAACACCTACGATTACATGAACAAGCGAGTG GTGGCCCCGGGGCTGGTGGACTGCTACATCAACCTGGGCGCGCGCTGGTCGCTGGACTACATGGACA ACGTCAACCCCTTCAACCACCACCGCAATGCGGGCCTGCGCTACCGCTCCATGCTCCTGGGCAACGG GCGCTACGTGCCCTTCCACATCCAGGTGCCCCAGAAGTTCTTTGCCATCAAGAACCTCCTCCTCCTGC CGGGCTCCTACACCTACGAGTGGAACTTCAGGAAGGATGTCAACATGGTCCTCCAGAGCTCTCTGGG TAACGATCTCAGGGTGGACGGGGCCAGCATCAAGTTCGAGAGCATCTGCCTCTACGCCACCTTCTTC CCCATGGCCCACAACACGGCCTCCACGCTCGAGGCCATGCTCAGGAACGACACCAACGACCAGTCCT TCAATGACTACCTCTCCGCCGCCAACATGCTCTACCCCATACCCGCCAACGCCACCAACGTCCCCATC TCCATCCCCTCGCGCAACTGGGCGGCCTTCCGCGGCTGGGCCTTCACCCGCCTCAAGACCAAGGAGA CCCCCTCCCTGGGCTCGGGATTCGACCCCTACTACACCTACTCGGGCTCCATTCCCTACCTGGACGGC ACCTTCTACCTCAACCACACTTTCAAGAAGGTCTCGGTCACCTTCGACTCCTCGGTCAGCTGGCCGGG CAACGACCGTCTGCTCACCCCCAACGAGTTCGAGATCAAGCGCTCGGTCGACGGGGAGGGCTACAAC GTGGCCCAGTGCAACATGACCAAGGACTGGTTCCTGGTCCAGATGCTGGCCAACTACAACATCGGCT ACCAGGGCTTCTACATCCCAGAGAGCTACAAGGACAGGATGTACTCCTTCTTCAGGAACTTCCAGCC CATGAGCCGGCAGGTGGTGGACCAGACCAAGTACAAGGACTACCAGGAGGTGGGCATCATCCACCA GCACAACAACTCGGGCTTCGTGGGCTACCTCGCCCCCACCATGCGCGAGGGACAGGCCTACCCCGCC AACTTCCCCTATCCGCTCATAGGCAAGACCGCGGTCGACAGCATCACCCAGAAAAAGTTCCTCTGCG ACCGCACCCTCTGGCGCATCCCCTTCTCCAGCAACTTCATGTCCATGGGTGCGCTCTCGGACCTGGGC CAGAACTTGCTCTACGCCAACTCCGCCCACGCCCTCGACATGACCTTCGAGGTCGACCCCATGGACG AGCCCACCCTTCTCTATGTTCTGTTCGAAGTCTTTGACGTGGTCCGGGTCCACCAGCCGCACCGCGGC GTCATCGAGACCGTGTACCTGCGTACGCCCTTCTCGGCCGGCAACGCCACCACCTAAAGAAGCAAGC CGCAGTCATCGCCGCCTGCATGCCGTCGGGTTCCACCGAGCAAGAGCTCAGGGCCATCGTCAGAGAC CTGGGATGCGGGCCCTATTTTTTGGGCACCTTCGACAAGCGCTTCCCTGGCTTTGTCTCCCCACACAA GCTGGCCTGCGCCATCGTCAACACGGCCGGCCGCGAGACCGGGGGCGTGCACTGGCTGGCCTTCGCC TGGAACCCGCGCTCCAAAACATGCTTCCTCTTTGACCCCTTCGGCTTTTCGGACCAGCGGCTCAAGCA AATCTACGAGTTCGAGTACGAGGGCTTGCTGCGTCGCAGCGCCATCGCCTCCTCGCCCGACCGCTGC GTCACCCTCGAAAAGTCCACCCAGACCGTGCAGGGGCCCGACTCGGCCGCCTGCGGTCTCTTCTGCT GCATGTTTCTGCACGCCTTTGTGCACTGGCCTCAGAGTCCCATGGACCGCAACCCCACCATGAACTTG CTGACGGGGGTGCCCAACTCCATGCTCCAGAGCCCCCAGGTCGAGCCCACCCTGCGCCGCAACCAGG AGCAGCTCTACAGCTTCCTGGAGCGCCACTCGCCTTACTTCCGCCGCCACAGCGCACAGATCAGGAG GGCCACCTCCTTCTGCCACTTGCAAGAGATGCAAGAAGGGTAATAACGATGTACACACTTTTTTTCTC AATAAATGGCATCTTTTTATTTATACAAGCTCTCTGGGGTATTCATTTCCCACCACCACCCGCCGTTGT CGCCATCTGGCTCTATTTAGAAATCGAAAGGGTTCTGCCGGGAGTCGCCGTGCGCCACGGGCAGGGA CACGTTGCGATACTGGTAGCGGGTGCCCCACTTGAACTCGGGCACCACCAGGCGAGGCAGCTCGGGG AAGTTTTCGCTCCACAGGCTGCGGGTCAGCACCAGCGCGTTCATCAGGTCGGGCGCCGAGATCTTGA AGTCGCAGTTGGGGCCGCCGCCCTGCGCGCGCGAGTTGCGGTACACCGGGTTGCAGCACTGGAACAC CAACAGCGCCGGGTGCTTCACGCTGGCCAGCACGCTGCGGTCGGAGATCAGCTCGGCGTCCAGGTCC TCCGCGTTGCTCAGCGCGAACGGGGTCATCTTGGGCACTTGCCGCCCCAGGAAGGGCGCGTGCCCCG GTTTCGAGTTGCAGTCGCAGCGCAGCGGGATCAGCAGGTGCCCGTGCCCGGACTCGGCGTTGGGGTA CAGCGCGCGCATGAAGGCCTGCATCTGGCGGAAGGCCATCTGGGCCTTGGCGCCCTCCGAGAAGAAC ATGCCGCAGGACTTGCCCGAGAACTGGTTTGCGGGGCAGCTGGCGTCGTGCAGGCAGCAGCGCGCGT CGGTGTTGGCGATCTGCACCACGTTGCGCCCCCACCGGTTCTTCACGATCTTGGCCTTGGACGATTGC TCCTTCAGCGCGCGCTGCCCGTTCTCGCTGGTCACATCCATCTCGATCACATGTTCCTTGTTCACCATG CTGCTGCCGTGCAGACACTTCAGCTCGCCCTCCGTCTCGGTGCAGCGGTGCTGCCACAGCGCGCAGC CCGTGGGCTCGAAAGACTTGTAGGTCACCTCCGCGAAGGACTGCAGGTACCCCTGCAAAAAGCGGCC CATCATGGTCACGAAGGTCTTGTTGCTGCTGAAGGTCAGCTGCAGCCCGCGGTGCTCCTCGTTCAGCC AGGTCTTGCACACGGCCGCCAGCGCCTCCACCTGGTCGGGCAGCATCTTGAAGTTCACCTTCAGCTCA TTCTCCACGTGGTACTTGTCCATCAGCGTGCGCGCCGCCTCCATGCCCTTCTCCCAGGCCGACACCAG CGGCAGGCTCACGGGGTTCTTCACCATCACCGTGGCCGCCGCCTCCGCCGCGCTTTCGCTTTCCGCCC CGCTGTTCTCTTCCTCTTCCTCCTCTTCCTCGCCGCCGCCCACTCGCAGCCCCCGCACCACGGGGTCGT CTTCCTGCAGGCGCTGCACCTTGCGCTTGCCGTTGCGCCCCTGCTTGATGCGCACGGGCGGGTTGCTG AAGCCCACCATCACCAGCGCGGCCTCTTCTTGCTCGTCCTCGCTGTCCAGAATGACCTCCGGGGAGG GGGGGTTGGTCATCCTCAGTACCGAGGCACGCTTCTTTTTCTTCCTGGGGGCGTTCGCCAGCTCCGCG GCTGCGGCCGCTGCCGAGGTCGAAGGCCGAGGGCTGGGCGTGCGCGGCACCAGCGCGTCCTGCGAG CCGTCCTCGTCCTCCTCGGACTCGAGACGGAGGCGGGCCCGCTTCTTCGGGGGCGCGCGGGGCGGCG GAGGCGGCGGCGGCGACGGAGACGGGGACGAGACATCGTCCAGGGTGGGTGGACGGCGGGCCGCG CCGCGTCCGCGCTCGGGGGTGGTCTCGCGCTGGTCCTCTTCCCGACTGGCCATCTCCCACTGCTCCTT CTCCTATAGGCAGAAAGAGATCATGGAGTCTCTCATGCGAGTCGAGAAGGAGGAGGACAGCCTAAC CGCCCCCTCTGAGCCCTCCACCACCGCCGCCACCACCGCCAATGCCGCCGCGGACGACGCGCCCACC GAGACCACCGCCAGTACCACCCTCCCCAGCGACGCACCCCCGCTCGAGAATGAAGTGCTGATCGAGC AGGACCCGGGTTTTGTGAGCGGAGAGGAGGATGAGGTGGATGAGAAGGAGAAGGAGGAGGTCGCC GCCTCAGTGCCAAAAGAGGATAAAAAGCAAGACCAGGACGACGCAGATAAGGATGAGACAGCAGT CGGGCGGGGGAACGGAAGCCATGATGCTGATGACGGCTACCTAGACGTGGGAGACGACGTGCTGCT TAAGCACCTGCACCGCCAGTGCGTCATCGTCTGCGACGCGCTGCAGGAGCGCTGCGAAGTGCCCCTG GACGTGGCGGAGGTCAGCCGCGCCTACGAGCGGCACCTCTTCGCGCCGCACGTGCCCCCCAAGCGCC GGGAGAACGGCACCTGCGAGCCCAACCCGCGTCTCAACTTCTACCCGGTCTTCGCGGTACCCGAGGT GCTGGCCACCTACCACATCTTTTTCCAAAACTGCAAGATCCCCCTCTCCTGCCGCGCCAACCGCACCC GCGCCGACAAAACCCTGACCCTGCGGCAGGGCGCCCACATACCTGATATCGCCTCTCTGGAGGAAGT GCCCAAGATCTTCGAGGGTCTCGGTCGCGACGAGAAACGGGCGGCGAACGCTCTGCACGGAGACAG CGAAAACGAGAGTCACTCGGGGGTGCTGGTGGAGCTCGAGGGCGACAACGCGCGCCTGGCCGTACT CAAGCGCAGCATAGAGGTCACCCACTTTGCCTACCCGGCGCTCAACCTGCCCCCCAAGGTCATGAGT GTGGTCATGGGCGAGCTCATCATGCGCCGCGCCCAGCCCCTGGCCGCGGATGCAAACTTGCAAGAGT CCTCCGAGGAAGGCCTGCCCGCGGTCAGCGACGAGCAGCTGGCGCGCTGGCTGGAGACCCGCGACC CCGCGCAGCTGGAGGAGCGGCGCAAGCTCATGATGGCCGCGGTGCTGGTCACCGTGGAGCTCGAGT GTCTGCAGCGCTTCTTCGCGGACCCCGAGATGCAGCGCAAGCTCGAGGAGACCCTGCACTACACCTT CCGCCAGGGCTACGTGCGCCAGGCCTGCAAGATCTCCAACGTGGAGCTCTGCAACCTGGTCTCCTAC CTGGGCATCCTGCACGAGAACCGCCTCGGGCAGAACGTCCTGCACTCCACCCTCAAAGGGGAGGCGC GCCGCGACTACATCCGCGACTGCGCCTACCTCTTCCTCTGCTACACCTGGCAGACGGCCATGGGGGTC TGGCAGCAGTGCCTGGAGGAGCGCAACCTCAAGGAGCTGGAAAAGCTCCTCAAGCGCACCCTCAGG GACCTCTGGACGGGCTTCAACGAGCGCTCGGTGGCCGCCGCGCTGGCGGACATCATCTTTCCCGAGC GCCTGCTCAAGACCCTGCAGCAGGGCCTGCCCGACTTCACCAGCCAGAGCATGCTGCAGAACTTCAG GACTTTCATCCTGGAGCGCTCGGGCATCCTGCCGGCCACTTGCTGCGCGCTGCCCAGCGACTTCGTGC CCATCAAGTACAGGGAGTGCCCGCCGCCGCTCTGGGGCCACTGCTACCTCTTCCAGCTGGCCAACTA CCTCGCCTACCACTCGGACCTCATGGAAGACGTGAGCGGCGAGGGCCTGCTCGAGTGCCACTGCCGC TGCAACCTCTGCACGCCCCACCGCTCTCTAGTCTGCAACCCGCAGCTGCTCAGCGAGAGTCAGATTAT CGGTACCTTCGAGCTGCAGGGTCCCTCGCCTGACGAGAAGTCCGCGGCTCCAGGGCTGAAACTCACT CCGGGGCTGTGGACTTCCGCCTACCTACGCAAATTTGTACCTGAGGACTACCACGCCCACGAGATCA GGTTCTACGAAGACCAATCCCGCCCGCCCAAGGCGGAGCTCACCGCCTGCGTCATCACCCAGGGGCA CATCCTGGGCCAATTGCAAGCCATCAACAAAGCCCGCCGAGAGTTCTTGCTGAAAAAGGGTCGGGGG GTGTACCTGGACCCCCAGTCCGGCGAGGAGCTAAACCCGCTACCCCCGCCGCCGCCCCAGCAGCGGG ACCTTGCTTCCCAGGATGGCACCCAGAAAGAAGCAGCAGCCGCCGCCGCCGCCGCAGCCATACATGC TTCTGGAGGAAGAGGAGGAGGACTGGGACAGTCAGGCAGAGGAGGTTTCGGACGAGGAGCAGGAG GAGATGATGGAAGACTGGGAGGAGGACAGCAGCCTAGACGAGGAAGCTTCAGAGGCCGAAGAGGT GGCAGACGCAACACCATCGCCCTCGGTCGCAGCCCCCTCGCCGGGGCCCCTGAAATCCTCCGAACCC AGCACCAGCGCTATAACCTCCGCTCCTCCGGCGCCGGCGCCACCCGCCCGCAGACCCAACCGTAGAT GGGACACCACAGGAACCGGGGTCGGTAAGTCCAAGTGCCCGCCGCCGCCACCGCAGCAGCAGCAGC AGCAGCGCCAGGGCTACCGCTCGTGGCGCGGGCACAAGAACGCCATAGTCGCCTGCTTGCAAGACTG CGGGGGCAACATCTCTTTCGCCCGCCGCTTCCTGCTATTCCACCACGGGGTCGCCTTTCCCCGCAATG TCCTGCATTACTACCGTCATCTCTACAGCCCCTACTGCAGCGGCGACCCAGAGGCGGCAGCGGCAGC CACAGCGGCGACCACCACCTAGGAAGATATCCTCCGCGGGCAAGACAGCGGCAGCAGCGGCCAGGA GACCCGCGGCAGCAGCGGCGGGAGCGGTGGGCGCACTGCGCCTCTCGCCCAACGAACCCCTCTCGAC CCGGGAGCTCAGACACAGGATCTTCCCCACTTTGTATGCCATCTTCCAACAGAGCAGAGGCCAGGAG CAGGAGCTGAAAATAAAAAACAGATCTCTGCGCTCCCTCACCCGCAGCTGTCTGTATCACAAAAGCG AAGATCAGCTTCGGCGCACGCTGGAGGACGCGGAGGCACTCTTCAGCAAATACTGCGCGCTCACTCT TAAAGACTAGCTCCGCGCCCTTCTCGAATTTAGGCGGGAGAAAACTACGTCATCGCCGGCCGCCGCC CAGCCCGCCCAGCCGAGATGAGCAAAGAGATTCCCACGCCATACATGTGGAGCTACCAGCCGCAGA TGGGACTCGCGGCGGGAGCGGCCCAGGACTACTCCACCCGCATGAACTACATGAGCGCGGGACCCC ACATGATCTCACAGGTCAACGGGATCCGCGCCCAGCGAAACCAAATACTGCTGGAACAGGCGGCCA TCACCGCCACGCCCCGCCATAATCTCAACCCCCGAAATTGGCCCGCCGCCCTCGTGTACCAGGAAAC CCCCTCCGCCACCACCGTACTACTTCCGCGTGACGCCCAGGCCGAAGTCCAGATGACTAACTCAGGG GCGCAGCTCGCGGGCGGCTTTCGTCACGGGGCGCGGCCGCTCCGACCAGGTATAAGACACCTGATGA TCAGAGGCCGAGGTATCCAGCTCAACGACGAGTCGGTGAGCTCTTCGCTCGGTCTCCGTCCGGACGG AACTTTCCAGCTCGCCGGATCCGGCCGCTCTTCGTTCACGCCCCGCCAGGCGTACCTGACTCTGCAGA CCTCGTCCTCGGAGCCCCGCTCCGGCGGCATCGGAACCCTCCAGTTCGTGGAGGAGTTCGTGCCCTCG GTCTACTTCAACCCCTTCTCGGGACCTCCCGGACGCTACCCCGACCAGTTCATTCCGAACTTTGACGC GGTGAAGGACTCGGCGGACGGCTACGACTGAATGTCAGGTGTCGAGGCAGAGCAGCTTCGCCTGAG ACACCTCGAGCACTGCCGCCGCCACAAGTGCTTCGCCCGCGGTTCTGGTGAGTTCTGCTACTTTCAGC TACCCGAGGAGCATACCGAGGGGCCGGCGCACGGCGTCCGCCTGACCACCCAGGGCGAGGTTACCT GTTCCCTCATCCGGGAGTTTACCCTCCGTCCCCTGCTAGTGGAGCGGGAGCGGGGTCCCTGTGTCCTA ACTATCGCCTGCAACTGCCCTAACCCTGGATTACATCAAGATCTTTGCTGTCATCTCTGTGCTGAGTTT AATAAACGCTGAGATCAGAATCTACTGGGGCTCCTGTCGCCATCCTGTGAACGCCACCGTCTTCACCC ACCCCGACCAGGCCCAGGCGAACCTCACCTGCGGTCTGCATCGGAGGGCCAAGAAGTACCTCACCTG GTACTTCAACGGCACCCCCTTTGTGGTTTACAACAGCTTCGACGGGGACGGAGTCTCCCTGAAAGAC CAGCTCTCCGGTCTCAGCTACTCCATCCACAAGAACACCACCCTCCAACTCTTCCCTCCCTACCTGCC GGGAACCTACGAGTGCGTCACCGGCCGCTGCACCCACCTCACCCGCCTGATCGTAAACCAGAGCTTT CCGGGAACAGATAACTCCCTCTTCCCCAGAACAGGAGGTGAGCTCAGGAAACTCCCCGGGGACCAG GGCGGAGACGTACCTTCGACCCTTGTGGGGTTAGGATTTTTTATTACCGGGTTGCTGGCTCTTTTAAT CAAAGTTTCCTTGAGATTTGTTCTTTCCTTCTACGTGTATGAACACCTCAACCTCCAATAACTCTACCC TTTCTTCGGAATCAGGTGACTTCTCTGAAATCGGGCTTGGTGTGCTGCTTACTCTGTTGATTTTTTTCC TTATCATACTCAGCCTTCTGTGCCTCAGGCTCGCCGCCTGCTGCGCACACATCTATATCTACTGCTGGT TGCTCAAGTGCAGGGGTCGCCACCCAAGATGAACAGGTACATGGTCCTATCGATCCTAGGCCTGCTG GCCCTGGCGGCCTGCAGCGCCGCCAAAAAAGAGATTACCTTTGAGGAGCCCGCTTGCAATGTAACTT TCAAGCCCGAGGGTGACCAATGCACCACCCTCGTCAAATGCGTTACCAATCATGAGAGGCTGCGCAT CGACTACAAAAACAAAACTGGCCAGTTTGCGGTCTATAGTGTGTTTACGCCCGGAGACCCCTCTAAC TACTCTGTCACCGTCTTCCAGGGCGGACAGTCTAAGATATTCAATTACACTTTCCCTTTTTATGAGTTA TGCGATGCGGTCATGTACATGTCAAAACAGTACAACCTGTGGCCTCCCTCTCCCCAGGCGTGTGTGG AAAATACTGGGTCTTACTGCTGTATGGCTTTCGCAATCACTACGCTCGCTCTAATCTGCACGGTGCTA TACATAAAATTCAGGCAGAGGCGAATCTTTATCGATGAAAAGAAAATGCCTTGATCGCTAACACCGG CTTTCTATCTGCAGAATGAATGCAATCACCTCCCTACTAATCACCACCACCCTCCTTGCGATTGCCCA TGGGTTGACACGAATCGAAGTGCCAGTGGGGTCCAATGTCACCATGGTGGGCCCCGCCGGCAATTCC ACCCTCATGTGGGAAAAATTTGTCCGCAATCAATGGGTTCATTTCTGCTCTAACCGAATCAGTATCAA GCCCAGAGCCATCTGCGATGGGCAAAATCTAACTCTGATCAATGTGCAAATGATGGATGCTGGGTAC TATTACGGGCAGCGGGGAGAAATCATTAATTACTGGCGACCCCACAAGGACTACATGCTGCATGTAG TCGAGGCACTTCCCACTACCACCCCCACTACCACCTCTCCCACCACCACCACCACTACTACTACTACT ACTACTACTACTACTACTACCACTACCGCTGCCCGCCATACCCGCAAAAGCACCATGATTAGCACAA AGCCCCCTCGTGCTCACTCCCACGCCGGCGGGCCCATCGGTGCGACCTCAGAAACCACCGAGCTTTG CTTCTGCCAATGCACTAACGCCAGCGCTCATGAACTGTTCGACCTGGAGAATGAGGATGTCCAGCAG AGCTCCGCTTGCCTGACCCAGGAGGCTGTGGAGCCCGTTGCCCTGAAGCAGATCGGTGATTCAATAA TTGACTCTTCTTCTTTTGCCACTCCCGAATACCCTCCCGATTCTACTTTCCACATCACGGGTACCAAAG ACCCTAACCTCTCTTTCTACCTGATGCTGCTGCTCTGTATCTCTGTGGTCTCTTCCGCGCTGATGTTAC TGGGGATGTTCTGCTGCCTGATCTGCCGCAGAAAGAGAAAAGCTCGCTCTCAGGGCCAACCACTGAT GCCCTTCCCCTACCCCCCGGATTTTGCAGATAACAAGATATGAGCTCGCTGCTGACACTAACCGCTTT ACTAGCCTGCGCTCTAACCCTTGTCGCTTGCGACTCGAGATTCCACAATGTCACAGCTGTGGCAGGAG AAAATGTTACTTTCAACTCCACGGCCGATACCCAGTGGTCGTGGAGTGGCTCAGGTAGCTACTTAACT ATCTGCAATAGCTCCACTTCCCCCGGCATATCCCCAACCAAGTACCAATGCAATGCCAGCCTGTTCAC CCTCATCAACGCTTCCACCCTGGACAATGGACTCTATGTAGGCTATGTACCCTTTGGTGGGCAAGGAA AGACCCACGCTTACAACCTGGAAGTTCGCCAGCCCAGAACCACTACCCAAGCTTCTCCCACCACCAC CACCACCACCACCATCACCAGCAGCAGCAGCAGCAGCAGCCACAGCAGCAGCAGCAGATTATTGAC TTTGGTTTTGGCCAGCTCATCTGCCGCTACCCAGGCCATCTACAGCTCTGTGCCCGAAACCACTCAGA TCCACCGCCCAGAAACGACCACCGCCACCACCCTACACACCTCCAGCGATCAGATGCCGACCAACAT CACCCCCTTGGCTCTTCAAATGGGACTTACAAGCCCCACTCCAAAACCAGTGGATGCGGCCGAGGTC TCCGCCCTCGTCAATGACTGGGCGGGGCTGGGAATGTGGTGGTTCGCCATAGGCATGATGGCGCTCT GCCTGCTTCTGCTCTGGCTCATCTGCTGCCTCCACCGCAGGCGAGCCAGACCCCCCATCTATAGACCC ATCATTGTCCTGAACCCCGATAATGATGGGATCCATAGATTGGATGGCCTGAAAAACCTACTTTTTTC TTTTACAGTATGATAAATTGAGACATGCCTCGCATTTTCTTGTACATGTTCCTTCTCCCACCTTTTCTG GGGTGTTCTACGCTGGCCGCTGTGTCTCACCTGGAGGTAGACTGCCTCTCACCCTTCACTGTCTACCT GCTTTACGGATTGGTCACCCTCACTCTCATCTGCAGCCTAATCACAGTAATCATCGCCTTCATCCAGT GCATTGATTACATCTGTGTGCGCCTCGCATACTTCAGACACCACCCGCAGTACCGAGACAGGAACAT TGCCCAACTTCTAAGACTGCTCTAATCATGCATAAGACTGTGATCTGCCTTCTGATCCTCTGCATCCT GCCCACCCTCACCTCCTGCCAGTACACCACAAAATCTCCGCGCAAAAGACATGCCTCCTGCCGCTTCA CCCAACTGTGGAATATACCCAAATGCTACAACGAAAAGAGCGAGCTCTCCGAAGCTTGGCTGTATGG GGTCATCTGTGTCTTAGTTTTCTGCAGCACTGTCTTTGCCCTCATAATCTACCCCTACTTTGATTTGGG ATGGAACGCGATCGATGCCATGAATTACCCCACCTTTCCCGCACCCGAGATAATTCCACTGCGACAA GTTGTACCCGTTGTCGTTAATCAACGCCCCCCATCCCCTACGCCCACTGAAATCAGCTACTTTAACCT AACAGGCGGAGATGACTGACGCCCTAGATCTAGAAATGGACGGCATCAGTACCGAGCAGCGTCTCCT AGAGAGGCGCAGGCAGGCGGCTGAGCAAGAGCGCCTCAATCAGGAGCTCCGAGATCTCGTTAACCT GCACCAGTGCAAAAGAGGCATCTTTTGTCTGGTAAAGCAGGCCAAAGTCACCTACGAGAAGACCGG CAACAGCCACCGCCTCAGTTACAAATTGCCCACCCAGCGCCAGAAGCTGGTGCTCATGGTGGGTGAG AATCCCATCACCGTCACCCAGCACTCGGTAGAGACCGAGGGGTGTCTGCACTCCCCCTGTCGGGGTC CAGAAGACCTCTGCACCCTGGTAAAGACCCTGTGCGGTCTCAGAGATTTAGTCCCCTTTAACTAATCA AACACTGGAATCAATAAAAAGAATCACTTACTTAAAATCAGACAGCAGGTCTCTGTCCAGTTTATTC AGCAGCACCTCCTTCCCCTCCTCCCAACTCTGGTACTCCAAACGCCTTCTGGCGGCAAACTTCCTCCA CACCCTGAAGGGAATGTCAGATTCTTGCTCCTGTCCCTCCGCACCCACTATCTTCATGTTGTTGCAGA TGAAGCGCACCAAAACGTCTGACGAGAGCTTCAACCCCGTGTACCCCTATGACACGGAAAGCGGCCC TCCCTCCGTCCCTTTCCTCACCCCTCCCTTCGTGTCTCCCGATGGATTCCAAGAAAGTCCCCCCGGGGT CCTGTCTCTGAACCTGGCCGAGCCCCTGGTCACTTCCCACGGCATGCTCGCCCTGAAAATGGGAAGT GGCCTCTCCCTGGACGACGCTGGCAACCTCACCTCTCAAGATATCACCACCGCTAGCCCTCCCCTCAA AAAAACCAAGACCAACCTCAGCCTAGAAACCTCATCCCCCCTAACTGTGAGCACCTCAGGCGCCCTC ACCGTAGCAGCCGCCGCTCCCCTGGCGGTGGCCGGCACCTCCCTCACCATGCAATCAGAGGCCCCCC TGACAGTACAGGATGCAAAACTCACCCTGGCCACCAAAGGCCCCCTGACCGTGTCTGAAGGCAAACT GGCCTTGCAAACATCGGCCCCGCTGACGGCCGCTGACAGCAGCACCCTCACAGTCAGTGCCACACCA CCCCTTAGCACAAGCAATGGCAGCTTGGGTATTGACATGCAAGCCCCCATTTACACCACCAATGGAA AACTAGGACTTAACTTTGGCGCTCCCCTGCATGTGGTAGACAGCCTAAATGCACTGACTGTAGTTACT GGCCAAGGTCTTACGATAAACGGAACAGCCCTACAAACTAGAGTCTCAGGTGCCCTCAACTATGACA CATCAGGAAACCTAGAATTGAGAGCTGCAGGGGGTATGCGAGTTGATGCAAATGGTCAACTTATCCT TGATGTAGCTTACCCATTTGATGCACAAAACAATCTCAGCCTTAGGCTTGGACAGGGACCCCTGTTTG TTAACTCTGCCCACAACTTGGATGTTAACTACAACAGAGGCCTCTACCTGTTCACATCTGGAAATACC AAAAAGCTAGAAGTTAATATCAAAACAGCCAAGGGTCTCATTTATGATGACACTGCTATAGCAATCA ATGCGGGTGATGGGCTACAGTTTGACTCAGGCTCAGATACAAATCCATTAAAAACTAAACTTGGATT AGGACTGGATTATGACTCCAGCAGAGCCATAATTGCTAAACTGGGAACTGGCCTAAGCTTTGACAAC ACAGGTGCCATCACAGTAGGCAACAAAAATGATGACAAGCTTACCTTGTGGACCACACCAGACCCAT CCCCTAACTGTAGAATCTATTCAGAGAAAGATGCTAAATTCACACTTGTTTTGACTAAATGCGGCAGT CAGGTGTTGGCCAGCGTTTCTGTTTTATCTGTAAAAGGTAGCCTTGCGCCCATCAGTGGCACAGTAAC TAGTGCTCAGATTGTCCTCAGATTTGATGAAAATGGAGTTCTACTAAGCAATTCTTCCCTTGACCCTC AATACTGGAACTACAGAAAAGGTGACCTTACAGAGGGCACTGCATATACCAACGCAGTGGGATTTAT GCCCAACCTCACAGCATACCCAAAAACACAGAGCCAAACTGCTAAAAGCAACATTGTAAGTCAGGTT TACTTGAATGGGGACAAATCCAAACCCATGACCCTCACCATTACCCTCAATGGAACTAATGAAACAG GAGATGCCACAGTAAGCACTTACTCCATGTCATTCTCATGGAACTGGAATGGAAGTAATTACATTAA TGAAACGTTCCAAACCAACTCCTTCACCTTCTCCTACATCGCCCAAGAATAAAAAGCATGACGCTGTT GATTTGATTCAATGTGTTTCTGTTTTATTTTCAAGCACAACAAAATCATTCAAGTCATTCTTCCATCTT AGCTTAATAGACACAGTAGCTTAATAGACCCAGTAGTGCAAAGCCCCATTCTAGCTTATAACTAGTG GAGAAGTACTCGCCTACATGGGGGTAGAGTCATAATCGTGCATCAGGATAGGGCGGTGGTGCTGCAG CAGCGCGCGAATAAACTGCTGCCGCCGCCGCTCCGTCCTGCAGGAATACAACATGGCAGTGGTCTCC TCAGCGATGATTCGCACCGCCCGCAGCATAAGGCGCCTTGTCCTCCGGGCACAGCAGCGCACCCTGA TCTCACTTAAATCAGCACAGTAACTGCAGCACAGCACCACAATATTGTTCAAAATCCCACAGTGCAA GGCGCTGTATCCAAAGCTCATGGCGGGGACCACAGAACCCACGTGGCCATCATACCACAAGCGCAG GTAGATTAAGTGGCGACCCCTCATAAACACGCTGGACATAAACATTACCTCTTTTGGCATGTTGTAAT TCACCACCTCCCGGTACCATATAAACCTCTGATTAAACATGGCGCCATCCACCACCATCCTAAACCAG CTGGCCAAAACCTGCCCGCCGGCTATACACTGCAGGGAACCGGGACTGGAACAATGACAGTGGAGA GCCCAGGACTCGTAACCATGGATCATCATGCTCGTCATGATATCAATGTTGGCACAACACAGGCACA CGTGCATACACTTCCTCAGGATTACAAGCTCCTCCCGCGTTAGAACCATATCCCAGGGAACAACCCA TTCCTGAATCAGCGTAAATCCCACACTGCAGGGAAGACCTCGCACGTAACTCACGTTGTGCATTGTC AAAGTGTTACATTCGGGCAGCAGCGGATGATCCTCCAGTATGGTAGCGCGGGTTTCTGTCTCAAAAG GAGGTAGACGATCCCTACTGTACGGAGTGCGCCGAGACAACCGAGATCGTGTTGGTCGTAGTGTCAT GCCAAATGGAACGCCGGACGTAGTCATATTTCCTGAAGTCTTAGATCTCTCAACGCAGCACCAGCAC CAACACTTCGCAGTGTAAAAGGCCAAGTGCCGAGAGAGTATATATAGGAATAAAAAGTGACGTAAA CGGGCAAAGTCCAAAAAACGCCCAGAAAAACCGCACGCGAACCTACGCCCCGAAACGAAAGCCAAA AAACACTAGACACTCCCTTCCGGCGTCAACTTCCGCTTTCCCACGCTACGTCACTTGCCCCAGTCAAA CAAACTACATATCCCGAACTTCCAAGTCGCCACGCCCAAAACACCGCCTACACCTCCCCGCCCGCCG GCCCGCCCCCAAACCCGCCTCCCGCCCCGCGCCCCGCCCCGCGCCGCCCATCTCATTATCATATTGGC TTCAATCCAAAATAAGGTATATTATTGATGATGGTTTAAACGGATCCAATTCTTGAAGACGAAAGGG CCTCGTGATACGCCTATTTTTATAGGTTAATGTCATGATAATAATGGTTTCTTAGACGTCAGGTGGCA CTTTTCGGGGAAATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGC TCATGAGACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGTATGAGTATTCAACA TTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGCTCACCCAGAAACGCTG GTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCTCAACA GCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCACTTTTAAAGTTCTG CTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTATT CTCAGAATGACTTGGTTGAGTACTCACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAG AGAATTATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAACGATC GGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCATGTAACTCGCCTTGATCGTT GGGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGTAGCAATGG CAACAACGTTGCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAATAGA CTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTG CTGATAAATCTGGAGCCGGTGAGCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAA GCCCTCCCGTATCGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAG ATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAGACCAAGTTTACTCATATATACT TTAGATTGATTTAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACG TGAGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTT TTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGAT CAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTCC TTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTG CTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACG ATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGA GCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGA AGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGC TTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGA TTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGT TCCTGGCCTTTTGCTGGCCTTGAAGCTGTCCCTGATGGTCGTCATCTACCTGCCTGGACAGCATGGCC TGCAACGCGGGCATCCCGATGCCGCCGGAAGCGAGAAGAATCATAATGGGGAAGGCCATCCAGCCT CGCGTCGCAGATCCGAATTCGTTTAAAC Polynucleotide sequence encoding ChAd155#1390 backbone construct SEQ ID NO: 8 CATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAATGAGATGGGCGGCGCGGGGCG GGGCGCGGGGCGGGAGGCGGGTTTGGGGGCGGGCCGGCGGGCGGGGCGGTGTGGCGGAAGTGGAC TTTGTAAGTGTGGCGGATGTGACTTGCTAGTGCCGGGCGCGGTAAAAGTGACGTTTTCCGTGCGCGA CAACGCCCCCGGGAAGTGACATTTTTCCCGCGGTTTTTACCGGATGTTGTAGTGAATTTGGGCGTAAC CAAGTAAGATTTGGCCATTTTCGCGGGAAAACTGAAACGGGGAAGTGAAATCTGATTAATTTTGCGT TAGTCATACCGCGTAATATTTGTCTAGGGCCGAGGGACTTTGGCCGATTACGTGGAGGACTCGCCCA GGTGTTTTTTGAGGTGAATTTCCGCGTTCCGGGTCAAAGTCTGCGTTTTATTATTATAGGATATCCCAT TGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTT GACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATG GAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGT GGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCT ATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCC TACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCA ATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAG TTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAA TGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCTCCCTATCAGTGATAGAGATCT CCCTATCAGTGATAGAGATCGTCGACGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCAT CCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGCGGCCGGGAACGGTGCA TTGGAACGCGGATTCCCCGTGCCAAGAGTGAGATCTTCCGTTTATCTAGGTACCGGGCCCCCCCTCGA GGTCGACGGTATCGATAAGCTTCACGCTGCCGCAAGCACTCAGGGCGCAAGGGCTGCTAAAGGAAG CGGAACACGTAGAAAGCCAGTCCGCAGAAACGGTGCTGACCCCGGATGAATGTCAGCTACTGGGCT ATCTGGACAAGGGAAAACGCAAGCGCAAAGAGAAAGCAGGTAGCTTGCAGTGGGCTTACATGGCGA TAGCTAGACTGGGCGGTTTTATGGACAGCAAGCGAACCGGAATTGCCAGCTGGGGCGCCCTCTGGTA AGGTTGGGAAGCCCTGCAAAGTAAACTGGATGGCTTTCTTGCCGCCAAGGATCTGATGGCGCAGGGG ATCAAGATCTAACCAGGAGCTATTTAATGGCAACAGTTAACCAGCTGGTACGCAAACCACGTGCTCG CAAAGTTGCGAAAAGCAACGTGCCTGCGCTGGAAGCATGCCCGCAAAAACGTGGCGTATGTACTCGT GTATATACTACCACTCCTAAAAAACCGAACTCCGCGCTGCGTAAAGTATGCCGTGTTCGTCTGACTAA CGGTTTCGAAGTGACTTCCTACATCGGTGGTGAAGGTCACAACCTGCAGGAGCACTCCGTGATCCTG ATCCGTGGCGGTCGTGTTAAAGACCTCCCGGGTGTTCGTTACCACACCGTACGTGGTGCGCTTGACTG CTCCGGCGTTAAAGACCGTAAGCAGGCTCGTTCCAAGTATGGCGTGAAGCGTCCTAAGGCTTAATGG TAGATCTGATCAAGAGACAGGATGACGGTCGTTTCGCATGCTTGAACAAGATGGATTGCACGCAGGT TCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTG ATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGT GCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCG CAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCA GGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGC TGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACG TACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCA GCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCG ATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTG GGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCG AATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTAT CGCCTTCTTGACGAGTTCTTCTGAGCGGGACTCTGGGGTTCGAAATGACCGACCAAGCGACGCCCAA CCTGCCATCACGAGATTTCGATTCCACCGCCGCCTTCTATGAAAGGTTGGGCTTCGGAATCGTTTTCC GGGACGCCGGCTGGATGATCCTCCAGCGCGGGGATCTCATGCTGGAGTTCTTCGCCCACCCCGGGCT CGATCCCCTCGGGGGGAATCAGAATTCAGTCGACAGCGGCCGCGATCTGCTGTGCCTTCTAGTTGCC AGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTT CCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGT GGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT CTATGGCCGATCAGCGATCGCTGAGGTGGGTGAGTGGGCGTGGCCTGGGGTGGTCATGAAAATATAT AAGTTGGGGGTCTTAGGGTCTCTTTATTTGTGTTGCAGAGACCGCCGGAGCCATGAGCGGGAGCAGC AGCAGCAGCAGTAGCAGCAGCGCCTTGGATGGCAGCATCGTGAGCCCTTATTTGACGACGCGGATGC CCCACTGGGCCGGGGTGCGTCAGAATGTGATGGGCTCCAGCATCGACGGCCGACCCGTCCTGCCCGC AAATTCCGCCACGCTGACCTATGCGACCGTCGCGGGGACGCCGTTGGACGCCACCGCCGCCGCCGCC GCCACCGCAGCCGCCTCGGCCGTGCGCAGCCTGGCCACGGACTTTGCATTCCTGGGACCACTGGCGA CAGGGGCTACTTCTCGGGCCGCTGCTGCCGCCGTTCGCGATGACAAGCTGACCGCCCTGCTGGCGCA GTTGGATGCGCTTACTCGGGAACTGGGTGACCTTTCTCAGCAGGTCATGGCCCTGCGCCAGCAGGTCT CCTCCCTGCAAGCTGGCGGGAATGCTTCTCCCACAAATGCCGTTTAAGATAAATAAAACCAGACTCT GTTTGGATTAAAGAAAAGTAGCAAGTGCATTGCTCTCTTTATTTCATAATTTTCCGCGCGCGATAGGC CCTAGACCAGCGTTCTCGGTCGTTGAGGGTGCGGTGTATCTTCTCCAGGACGTGGTAGAGGTGGCTCT GGACGTTGAGATACATGGGCATGAGCCCGTCCCGGGGGTGGAGGTAGCACCACTGCAGAGCTTCATG CTCCGGGGTGGTGTTGTAGATGATCCAGTCGTAGCAGGAGCGCTGGGCATGGTGCCTAAAAATGTCC TTCAGCAGCAGGCCGATGGCCAGGGGGAGGCCCTTGGTGTAAGTGTTTACAAAACGGTTAAGTTGGG AAGGGTGCATTCGGGGAGAGATGATGTGCATCTTGGACTGTATTTTTAGATTGGCGATGTTTCCGCCC AGATCCCTTCTGGGATTCATGTTGTGCAGGACCACCAGTACAGTGTATCCGGTGCACTTGGGGAATTT GTCATGCAGCTTAGAGGGAAAAGCGTGGAAGAACTTGGAGACGCCTTTGTGGCCTCCCAGATTTTCC ATGCATTCGTCCATGATGATGGCAATGGGCCCGCGGGAGGCAGCTTGGGCAAAGATATTTCTGGGGT CGCTGACGTCGTAGTTGTGTTCCAGGGTGAGGTCGTCATAGGCCATTTTTACAAAGCGCGGGCGGAG GGTGCCCGACTGGGGGATGATGGTCCCCTCTGGCCCTGGGGCGTAGTTGCCCTCGCAGATCTGCATTT CCCAGGCCTTAATCTCGGAGGGGGGAATCATATCCACCTGCGGGGCGATGAAGAAAACGGTTTCCGG AGCCGGGGAGATTAACTGGGATGAGAGCAGGTTTCTAAGCAGCTGTGATTTTCCACAACCGGTGGGC CCATAAATAACACCTATAACCGGTTGCAGCTGGTAGTTTAGAGAGCTGCAGCTGCCGTCGTCCCGGA GGAGGGGGGCCACCTCGTTGAGCATGTCCCTGACGCGCATGTTCTCCCCGACCAGATCCGCCAGAAG GCGCTCGCCGCCCAGGGACAGCAGCTCTTGCAAGGAAGCAAAGTTTTTCAGCGGCTTGAGGCCGTCC GCCGTGGGCATGTTTTTCAGGGTCTGGCTCAGCAGCTCCAGGCGGTCCCAGAGCTCGGTGACGTGCT CTACGGCATCTCTATCCAGCATATCTCCTCGTTTCGCGGGTTGGGGCGACTTTCGCTGTAGGGCACCA AGCGGTGGTCGTCCAGCGGGGCCAGAGTCATGTCCTTCCATGGGCGCAGGGTCCTCGTCAGGGTGGT CTGGGTCACGGTGAAGGGGTGCGCTCCGGGCTGAGCGCTTGCCAAGGTGCGCTTGAGGCTGGTTCTG CTGGTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGCGTCGGCCAGGTAGCATTTGACCATGGTGTCATA GTCCAGCCCCTCCGCGGCGTGTCCCTTGGCGCGCAGCTTGCCCTTGGAGGTGGCGCCGCACGAGGGG CAGAGCAGGCTCTTGAGCGCGTAGAGCTTGGGGGCGAGGAAGACCGATTCGGGGGAGTAGGCGTCC GCGCCGCAGACCCCGCACACGGTCTCGCACTCCACCAGCCAGGTGAGCTCGGGGCGCGCCGGGTCAA AAACCAGGTTTCCCCCATGCTTTTTGATGCGTTTCTTACCTCGGGTCTCCATGAGGTGGTGTCCCCGCT CGGTGACGAAGAGGCTGTCCGTGTCTCCGTAGACCGACTTGAGGGGTCTTTTCTCCAGGGGGGTCCC TCGGTCTTCCTCGTAGAGGAACTCGGACCACTCTGAGACGAAGGCCCGCGTCCAGGCCAGGACGAAG GAGGCTATGTGGGAGGGGTAGCGGTCGTTGTCCACTAGGGGGTCCACCTTCTCCAAGGTGTGAAGAC ACATGTCGCCTTCCTCGGCGTCCAGGAAGGTGATTGGCTTGTAGGTGTAGGCCACGTGACCGGGGGT TCCTGACGGGGGGGTATAAAAGGGGGTGGGGGCGCGCTCGTCGTCACTCTCTTCCGCATCGCTGTCT GCGAGGGCCAGCTGCTGGGGTGAGTATTCCCTCTCGAAGGCGGGCATGACCTCCGCGCTGAGGTTGT CAGTTTCCAAAAACGAGGAGGATTTGATGTTCACCTGTCCCGAGGTGATACCTTTGAGGGTACCCGC GTCCATCTGGTCAGAAAACACGATCTTTTTATTGTCCAGCTTGGTGGCGAACGACCCGTAGAGGGCG TTGGAGAGCAGCTTGGCGATGGAGCGCAGGGTCTGGTTCTTGTCCCTGTCGGCGCGCTCCTTGGCCGC GATGTTGAGCTGCACGTACTCGCGCGCGACGCAGCGCCACTCGGGGAAGACGGTGGTGCGCTCGTCG GGCACCAGGCGCACGCGCCAGCCGCGGTTGTGCAGGGTGACCAGGTCCACGCTGGTGGCGACCTCGC CGCGCAGGCGCTCGTTGGTCCAGCAGAGACGGCCGCCCTTGCGCGAGCAGAAGGGGGGCAGGGGGT CGAGCTGGGTCTCGTCCGGGGGGTCCGCGTCCACGGTGAAAACCCCGGGGCGCAGGCGCGCGTCGA AGTAGTCTATCTTGCAACCTTGCATGTCCAGCGCCTGCTGCCAGTCGCGGGCGGCGAGCGCGCGCTC GTAGGGGTTGAGCGGCGGGCCCCAGGGCATGGGGTGGGTGAGTGCGGAGGCGTACATGCCGCAGAT GTCATAGACGTAGAGGGGCTCCCGCAGGACCCCGATGTAGGTGGGGTAGCAGCGGCCGCCGCGGAT GCTGGCGCGCACGTAGTCATACAGCTCGTGCGAGGGGGCGAGGAGGTCGGGGCCCAGGTTGGTGCG GGCGGGGCGCTCCGCGCGGAAGACGATCTGCCTGAAGATGGCATGCGAGTTGGAAGAGATGGTGGG GCGCTGGAAGACGTTGAAGCTGGCGTCCTGCAGGCCGACGGCGTCGCGCACGAAGGAGGCGTAGGA GTCGCGCAGCTTGTGTACCAGCTCGGCGGTGACCTGCACGTCGAGCGCGCAGTAGTCGAGGGTCTCG CGGATGATGTCATATTTAGCCTGCCCCTTCTTTTTCCACAGCTCGCGGTTGAGGACAAACTCTTCGCG GTCTTTCCAGTACTCTTGGATCGGGAAACCGTCCGGTTCCGAACGGTAAGAGCCTAGCATGTAGAAC TGGTTGACGGCCTGGTAGGCGCAGCAGCCCTTCTCCACGGGGAGGGCGTAGGCCTGCGCGGCCTTGC GGAGCGAGGTGTGGGTCAGGGCGAAGGTGTCCCTGACCATGACTTTGAGGTACTGGTGCTTGAAGTC GGAGTCGTCGCAGCCGCCCCGCTCCCAGAGCGAGAAGTCGGTGCGCTTCTTGGAGCGGGGGTTGGGC AGAGCGAAGGTGACATCGTTGAAGAGGATTTTGCCCGCGCGGGGCATGAAGTTGCGGGTGATGCGG AAGGGCCCCGGCACTTCAGAGCGGTTGTTGATGACCTGGGCGGCGAGCACGATCTCGTCGAAGCCGT TGATGTTGTGGCCCACGATGTAGAGTTCCAGGAAGCGGGGCCGGCCCTTTACGGTGGGCAGCTTCTT TAGCTCTTCGTAGGTGAGCTCCTCGGGCGAGGCGAGGCCGTGCTCGGCCAGGGCCCAGTCCGCGAGG TGCGGGTTGTCTCTGAGGAAGGACTTCCAGAGGTCGCGGGCCAGGAGGGTCTGCAGGCGGTCTCTGA AGGTCCTGAACTGGCGGCCCACGGCCATTTTTTCGGGGGTGATGCAGTAGAAGGTGAGGGGGTCTTG CTGCCAGCGGTCCCAGTCGAGCTGCAGGGCGAGGTCGCGCGCGGCGGTGACCAGGCGCTCGTCGCCC CCGAATTTCATGACCAGCATGAAGGGCACGAGCTGCTTTCCGAAGGCCCCCATCCAAGTGTAGGTCT CTACATCGTAGGTGACAAAGAGGCGCTCCGTGCGAGGATGCGAGCCGATCGGGAAGAACTGGATCT CCCGCCACCAGTTGGAGGAGTGGCTGTTGATGTGGTGGAAGTAGAAGTCCCGTCGCCGGGCCGAACA CTCGTGCTGGCTTTTGTAAAAGCGAGCGCAGTACTGGCAGCGCTGCACGGGCTGTACCTCATGCACG AGATGCACCTTTCGCCCGCGCACGAGGAAGCCGAGGGGAAATCTGAGCCCCCCGCCTGGCTCGCGGC ATGGCTGGTTCTCTTCTACTTTGGATGCGTGTCCGTCTCCGTCTGGCTCCTCGAGGGGTGTTACGGTG GAGCGGACCACCACGCCGCGCGAGCCGCAGGTCCAGATATCGGCGCGCGGCGGTCGGAGTTTGATG ACGACATCGCGCAGCTGGGAGCTGTCCATGGTCTGGAGCTCCCGCGGCGGCGGCAGGTCAGCCGGG AGTTCTTGCAGGTTCACCTCGCAGAGTCGGGCCAGGGCGCGGGGCAGGTCTAGGTGGTACCTGATCT CTAGGGGCGTGTTGGTGGCGGCGTCGATGGCTTGCAGGAGCCCGCAGCCCCGGGGGGCGACGACGG TGCCCCGCGGGGTGGTGGTGGTGGTGGCGGTGCAGCTCAGAAGCGGTGCCGCGGGCGGGCCCCCGG AGGTAGGGGGGGCTCCGGTCCCGCGGGCAGGGGCGGCAGCGGCACGTCGGCGTGGAGCGCGGGCAG GAGTTGGTGCTGTGCCCGGAGGTTGCTGGCGAAGGCGACGACGCGGCGGTTGATCTCCTGGATCTGG CGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCTTGAACCTGAAAGAGAGTTCGACAGAATCAATCT CGGTGTCATTGACCGCGGCCTGGCGCAGGATCTCCTGCACGTCTCCCGAGTTGTCTTGGTAGGCGATC TCGGCCATGAACTGCTCGATCTCTTCCTCCTGGAGGTCTCCGCGTCCGGCGCGTTCCACGGTGGCCGC CAGGTCGTTGGAGATGCGCCCCATGAGCTGCGAGAAGGCGTTGAGTCCGCCCTCGTTCCAGACTCGG CTGTAGACCACGCCCCCCTGGTCATCGCGGGCGCGCATGACCACCTGCGCGAGGTTGAGCTCCACGT GCCGCGCGAAGACGGCGTAGTTGCGCAGACGCTGGAAGAGGTAGTTGAGGGTGGTGGCGGTGTGCT CGGCCACGAAGAAGTTCATGACCCAGCGGCGCAACGTGGATTCGTTGATGTCCCCCAAGGCCTCCAG CCGTTCCATGGCCTCGTAGAAGTCCACGGCGAAGTTGAAAAACTGGGAGTTGCGCGCCGACACGGTC AACTCCTCCTCCAGAAGACGGATGAGCTCGGCGACGGTGTCGCGCACCTCGCGCTCGAAGGCTATGG GGATCTCTTCCTCCGCTAGCATCACCACCTCCTCCTCTTCCTCCTCTTCTGGCACTTCCATGATGGCTT CCTCCTCTTCGGGGGGTGGCGGCGGCGGCGGTGGGGGAGGGGGCGCTCTGCGCCGGCGGCGGCGCA CCGGGAGGCGGTCCACGAAGCGCGCGATCATCTCCCCGCGGCGGCGGCGCATGGTCTCGGTGACGGC GCGGCCGTTCTCCCGGGGGCGCAGTTGGAAGACGCCGCCGGACATCTGGTGCTGGGGCGGGTGGCCG TGAGGCAGCGAGACGGCGCTGACGATGCATCTCAACAATTGCTGCGTAGGTACGCCGCCGAGGGAC CTGAGGGAGTCCATATCCACCGGATCCGAAAACCTTTCGAGGAAGGCGTCTAACCAGTCGCAGTCGC AAGGTAGGCTGAGCACCGTGGCGGGCGGCGGGGGGTGGGGGGAGTGTCTGGCGGAGGTGCTGCTGA TGATGTAATTGAAGTAGGCGGACTTGACACGGCGGATGGTCGACAGGAGCACCATGTCCTTGGGTCC GGCCTGCTGGATGCGGAGGCGGTCGGCTATGCCCCAGGCTTCGTTCTGGCATCGGCGCAGGTCCTTG TAGTAGTCTTGCATGAGCCTTTCCACCGGCACCTCTTCTCCTTCCTCTTCTGCTTCTTCCATGTCTGCTT CGGCCCTGGGGCGGCGCCGCGCCCCCCTGCCCCCCATGCGCGTGACCCCGAACCCCCTGAGCGGTTG GAGCAGGGCCAGGTCGGCGACGACGCGCTCGGCCAGGATGGCCTGCTGCACCTGCGTGAGGGTGGT TTGGAAGTCATCCAAGTCCACGAAGCGGTGGTAGGCGCCCGTGTTGATGGTGTAGGTGCAGTTGGCC ATGACGGACCAGTTGACGGTCTGGTGGCCCGGTTGCGACATCTCGGTGTACCTGAGTCGCGAGTAGG CGCGGGAGTCGAAGACGTAGTCGTTGCAAGTCCGCACCAGGTACTGGTAGCCCACCAGGAAGTGCG GCGGCGGCTGGCGGTAGAGGGGCCAGCGCAGGGTGGCGGGGGCTCCGGGGGCCAGGTCTTCCAGCA TGAGGCGGTGGTAGGCGTAGATGTACCTGGACATCCAGGTGATACCCGCGGCGGTGGTGGAGGCGC GCGGGAAGTCGCGCACCCGGTTCCAGATGTTGCGCAGGGGCAGAAAGTGCTCCATGGTAGGCGTGCT CTGTCCAGTCAGACGCGCGCAGTCGTTGATACTCTAGACCAGGGAAAACGAAAGCCGGTCAGCGGG CACTCTTCCGTGGTCTGGTGAATAGATCGCAAGGGTATCATGGCGGAGGGCCTCGGTTCGAGCCCCG GGTCCGGGCCGGACGGTCCGCCATGATCCACGCGGTTACCGCCCGCGTGTCGAACCCAGGTGTGCGA CGTCAGACAACGGTGGAGTGTTCCTTTTGGCGTTTTTCTGGCCGGGCGCCGGCGCCGCGTAAGAGAC TAAGCCGCGAAAGCGAAAGCAGTAAGTGGCTCGCTCCCCGTAGCCGGAGGGATCCTTGCTAAGGGTT GCGTTGCGGCGAACCCCGGTTCGAATCCCGTACTCGGGCCGGCCGGACCCGCGGCTAAGGTGTTGGA TTGGCCTCCCCCTCGTATAAAGACCCCGCTTGCGGATTGACTCCGGACACGGGGACGAGCCCCTTTTA TTTTTGCTTTCCCCAGATGCATCCGGTGCTGCGGCAGATGCGCCCCCCGCCCCAGCAGCAGCAACAAC ACCAGCAAGAGCGGCAGCAACAGCAGCGGGAGTCATGCAGGGCCCCCTCACCCACCCTCGGCGGGC CGGCCACCTCGGCGTCCGCGGCCGTGTCTGGCGCCTGCGGCGGCGGCGGGGGGCCGGCTGACGACCC CGAGGAGCCCCCGCGGCGCAGGGCCAGACACTACCTGGACCTGGAGGAGGGCGAGGGCCTGGCGCG GCTGGGGGCGCCGTCTCCCGAGCGCCACCCGCGGGTGCAGCTGAAGCGCGACTCGCGCGAGGCGTA CGTGCCTCGGCAGAACCTGTTCAGGGACCGCGCGGGCGAGGAGCCCGAGGAGATGCGGGACAGGAG GTTCAGCGCAGGGCGGGAGCTGCGGCAGGGGCTGAACCGCGAGCGGCTGCTGCGCGAGGAGGACTT TGAGCCCGACGCGCGGACGGGGATCAGCCCCGCGCGCGCGCACGTGGCGGCCGCCGACCTGGTGAC GGCGTACGAGCAGACGGTGAACCAGGAGATCAACTTCCAAAAGAGTTTCAACAACCACGTGCGCAC GCTGGTGGCGCGCGAGGAGGTGACCATCGGGCTGATGCACCTGTGGGACTTTGTAAGCGCGCTGGTG CAGAACCCCAACAGCAAGCCTCTGACGGCGCAGCTGTTCCTGATAGTGCAGCACAGCAGGGACAAC GAGGCGTTTAGGGACGCGCTGCTGAACATCACCGAGCCCGAGGGTCGGTGGCTGCTGGACCTGATTA ACATCCTGCAGAGCATAGTGGTGCAGGAGCGCAGCCTGAGCCTGGCCGACAAGGTGGCGGCCATCA ACTACTCGATGCTGAGCCTGGGCAAGTTTTACGCGCGCAAGATCTACCAGACGCCGTACGTGCCCAT AGACAAGGAGGTGAAGATCGACGGTTTTTACATGCGCATGGCGCTGAAGGTGCTCACCCTGAGCGAC GACCTGGGCGTGTACCGCAACGAGCGCATCCACAAGGCCGTGAGCGTGAGCCGGCGGCGCGAGCTG AGCGACCGCGAGCTGATGCACAGCCTGCAGCGGGCGCTGGCGGGCGCCGGCAGCGGCGACAGGGAG GCGGAGTCCTACTTCGATGCGGGGGCGGACCTGCGCTGGGCGCCCAGCCGGCGGGCCCTGGAGGCC GCGGGGGTCCGCGAGGACTATGACGAGGACGGCGAGGAGGATGAGGAGTACGAGCTAGAGGAGGG CGAGTACCTGGACTAAACCGCGGGTGGTGTTTCCGGTAGATGCAAGACCCGAACGTGGTGGACCCGG CGCTGCGGGCGGCTCTGCAGAGCCAGCCGTCCGGCCTTAACTCCTCAGACGACTGGCGACAGGTCAT GGACCGCATCATGTCGCTGACGGCGCGTAACCCGGACGCGTTCCGGCAGCAGCCGCAGGCCAACAG GCTCTCCGCCATCCTGGAGGCGGTGGTGCCTGCGCGCTCGAACCCCACGCACGAGAAGGTGCTGGCC ATAGTGAACGCGCTGGCCGAGAACAGGGCCATCCGCCCGGACGAGGCCGGGCTGGTGTACGACGCG CTGCTGCAGCGCGTGGCCCGCTACAACAGCGGCAACGTGCAGACCAACCTGGACCGGCTGGTGGGG GACGTGCGCGAGGCGGTGGCGCAGCGCGAGCGCGCGGATCGGCAGGGCAACCTGGGCTCCATGGTG GCGCTGAATGCCTTCCTGAGCACGCAGCCGGCCAACGTGCCGCGGGGGCAGGAAGACTACACCAAC TTTGTGAGCGCGCTGCGGCTGATGGTGACCGAGACCCCCCAGAGCGAGGTGTACCAGTCGGGCCCGG ACTACTTCTTCCAGACCAGCAGACAGGGCCTGCAGACGGTGAACCTGAGCCAGGCTTTCAAGAACCT GCGGGGGCTGTGGGGCGTGAAGGCGCCCACCGGCGACCGGGCGACGGTGTCCAGCCTGCTGACGCC CAACTCGCGCCTGCTGCTGCTGCTGATCGCGCCGTTCACGGACAGCGGCAGCGTGTCCCGGGACACC TACCTGGGGCACCTGCTGACCCTGTACCGCGAGGCCATCGGGCAGGCGCAGGTGGACGAGCACACCT TCCAGGAGATCACCAGCGTGAGCCGCGCGCTGGGGCAGGAGGACACGAGCAGCCTGGAGGCGACTC TGAACTACCTGCTGACCAACCGGCGGCAGAAGATTCCCTCGCTGCACAGCCTGACCTCCGAGGAGGA GCGCATCTTGCGCTACGTGCAGCAGAGCGTGAGCCTGAACCTGATGCGCGACGGGGTGACGCCCAGC GTGGCGCTGGACATGACCGCGCGCAACATGGAACCGGGCATGTACGCCGCGCACCGGCCTTACATCA ACCGCCTGATGGACTACCTGCATCGCGCGGCGGCCGTGAACCCCGAGTACTTTACCAACGCCATCCT GAACCCGCACTGGCTCCCGCCGCCCGGGTTCTACAGCGGGGGCTTCGAGGTCCCGGAGACCAACGAT GGCTTCCTGTGGGACGACATGGACGACAGCGTGTTCTCCCCGCGGCCGCAGGCGCTGGCGGAAGCGT CCCTGCTGCGTCCCAAGAAGGAGGAGGAGGAGGAGGCGAGTCGCCGCCGCGGCAGCAGCGGCGTGG CTTCTCTGTCCGAGCTGGGGGCGGCAGCCGCCGCGCGCCCCGGGTCCCTGGGCGGCAGCCCCTTTCC GAGCCTGGTGGGGTCTCTGCACAGCGAGCGCACCACCCGCCCTCGGCTGCTGGGCGAGGACGAGTAC CTGAATAACTCCCTGCTGCAGCCGGTGCGGGAGAAAAACCTGCCTCCCGCCTTCCCCAACAACGGGA TAGAGAGCCTGGTGGACAAGATGAGCAGATGGAAGACCTATGCGCAGGAGCACAGGGACGCGCCTG CGCTCCGGCCGCCCACGCGGCGCCAGCGCCACGACCGGCAGCGGGGGCTGGTGTGGGATGACGAGG ACTCCGCGGACGATAGCAGCGTGCTGGACCTGGGAGGGAGCGGCAACCCGTTCGCGCACCTGCGCCC CCGCCTGGGGAGGATGTTTTAAAAAAAAAAAAAAAAAGCAAGAAGCATGATGCAAAAATTAAATAA AACTCACCAAGGCCATGGCGACCGAGCGTTGGTTTCTTGTGTTCCCTTCAGTATGCGGCGCGCGGCG ATGTACCAGGAGGGACCTCCTCCCTCTTACGAGAGCGTGGTGGGCGCGGCGGCGGCGGCGCCCTCTT CTCCCTTTGCGTCGCAGCTGCTGGAGCCGCCGTACGTGCCTCCGCGCTACCTGCGGCCTACGGGGGG GAGAAACAGCATCCGTTACTCGGAGCTGGCGCCCCTGTTCGACACCACCCGGGTGTACCTGGTGGAC AACAAGTCGGCGGACGTGGCCTCCCTGAACTACCAGAACGACCACAGCAATTTTTTGACCACGGTCA TCCAGAACAATGACTACAGCCCGAGCGAGGCCAGCACCCAGACCATCAATCTGGATGACCGGTCGC ACTGGGGCGGCGACCTGAAAACCATCCTGCACACCAACATGCCCAACGTGAACGAGTTCATGTTCAC CAATAAGTTCAAGGCGCGGGTGATGGTGTCGCGCTCGCACACCAAGGAAGACCGGGTGGAGCTGAA GTACGAGTGGGTGGAGTTCGAGCTGCCAGAGGGCAACTACTCCGAGACCATGACCATTGACCTGATG AACAACGCGATCGTGGAGCACTATCTGAAAGTGGGCAGGCAGAACGGGGTCCTGGAGAGCGACATC GGGGTCAAGTTCGACACCAGGAACTTCCGCCTGGGGCTGGACCCCGTGACCGGGCTGGTTATGCCCG GGGTGTACACCAACGAGGCCTTCCATCCCGACATCATCCTGCTGCCCGGCTGCGGGGTGGACTTCAC TTACAGCCGCCTGAGCAACCTCCTGGGCATCCGCAAGCGGCAGCCCTTCCAGGAGGGCTTCAGGATC ACCTACGAGGACCTGGAGGGGGGCAACATCCCCGCGCTCCTCGATGTGGAGGCCTACCAGGATAGCT TGAAGGAAAATGAGGCGGGACAGGAGGATACCGCCCCCGCCGCCTCCGCCGCCGCCGAGCAGGGCG AGGATGCTGCTGACACCGCGGCCGCGGACGGGGCAGAGGCCGACCCCGCTATGGTGGTGGAGGCTC CCGAGCAGGAGGAGGACATGAATGACAGTGCGGTGCGCGGAGACACCTTCGTCACCCGGGGGGAGG AAAAGCAAGCGGAGGCCGAGGCCGCGGCCGAGGAAAAGCAACTGGCGGCAGCAGCGGCGGCGGCG GCGTTGGCCGCGGCGGAGGCTGAGTCTGAGGGGACCAAGCCCGCCAAGGAGCCCGTGATTAAGCCC CTGACCGAAGATAGCAAGAAGCGCAGTTACAACCTGCTCAAGGACAGCACCAACACCGCGTACCGC AGCTGGTACCTGGCCTACAACTACGGCGACCCGTCGACGGGGGTGCGCTCCTGGACCCTGCTGTGCA CGCCGGACGTGACCTGCGGCTCGGAGCAGGTGTACTGGTCGCTGCCCGACATGATGCAAGACCCCGT GACCTTCCGCTCCACGCGGCAGGTCAGCAACTTCCCGGTGGTGGGCGCCGAGCTGCTGCCCGTGCAC TCCAAGAGCTTCTACAACGACCAGGCCGTCTACTCCCAGCTCATCCGCCAGTTCACCTCTCTGACCCA CGTGTTCAATCGCTTTCCTGAGAACCAGATTCTGGCGCGCCCGCCCGCCCCCACCATCACCACCGTCA GTGAAAACGTTCCTGCTCTCACAGATCACGGGACGCTACCGCTGCGCAACAGCATCGGAGGAGTCCA GCGAGTGACCGTTACTGACGCCAGACGCCGCACCTGCCCCTACGTTTACAAGGCCTTGGGCATAGTC TCGCCGCGCGTCCTTTCCAGCCGCACTTTTTGAGCAACACCACCATCATGTCCATCCTGATCTCACCC AGCAATAACTCCGGCTGGGGACTGCTGCGCGCGCCCAGCAAGATGTTCGGAGGGGCGAGGAAGCGT TCCGAGCAGCACCCCGTGCGCGTGCGCGGGCACTTCCGCGCCCCCTGGGGAGCGCACAAACGCGGCC GCGCGGGGCGCACCACCGTGGACGACGCCATCGACTCGGTGGTGGAGCAGGCGCGCAACTACAGGC CCGCGGTCTCTACCGTGGACGCGGCCATCCAGACCGTGGTGCGGGGCGCGCGGCGGTACGCCAAGCT GAAGAGCCGCCGGAAGCGCGTGGCCCGCCGCCACCGCCGCCGACCCGGGGCCGCCGCCAAACGCGC CGCCGCGGCCCTGCTTCGCCGGGCCAAGCGCACGGGCCGCCGCGCCGCCATGAGGGCCGCGCGCCGC TTGGCCGCCGGCATCACCGCCGCCACCATGGCCCCCCGTACCCGAAGACGCGCGGCCGCCGCCGCCG CCGCCGCCATCAGTGACATGGCCAGCAGGCGCCGGGGCAACGTGTACTGGGTGCGCGACTCGGTGAC CGGCACGCGCGTGCCCGTGCGCTTCCGCCCCCCGCGGACTTGAGATGATGTGAAAAAACAACACTGA GTCTCCTGCTGTTGTGTGTATCCCAGCGGCGGCGGCGCGCGCAGCGTCATGTCCAAGCGCAAAATCA AAGAAGAGATGCTCCAGGTCGTCGCGCCGGAGATCTATGGGCCCCCGAAGAAGGAAGAGCAGGATT CGAAGCCCCGCAAGATAAAGCGGGTCAAAAAGAAAAAGAAAGATGATGACGATGCCGATGGGGAG GTGGAGTTCCTGCGCGCCACGGCGCCCAGGCGCCCGGTGCAGTGGAAGGGCCGGCGCGTAAAGCGC GTCCTGCGCCCCGGCACCGCGGTGGTCTTCACGCCCGGCGAGCGCTCCACCCGGACTTTCAAGCGCG TCTATGACGAGGTGTACGGCGACGAAGACCTGCTGGAGCAGGCCAACGAGCGCTTCGGAGAGTTTGC TTACGGGAAGCGTCAGCGGGCGCTGGGGAAGGAGGACCTGCTGGCGCTGCCGCTGGACCAGGGCAA CCCCACCCCCAGTCTGAAGCCCGTGACCCTGCAGCAGGTGCTGCCGAGCAGCGCACCCTCCGAGGCG AAGCGGGGTCTGAAGCGCGAGGGCGGCGACCTGGCGCCCACCGTGCAGCTCATGGTGCCCAAGCGG CAGAGGCTGGAGGATGTGCTGGAGAAAATGAAAGTAGACCCCGGTCTGCAGCCGGACATCAGGGTC CGCCCCATCAAGCAGGTGGCGCCGGGCCTCGGCGTGCAGACCGTGGACGTGGTCATCCCCACCGGCA ACTCCCCCGCCGCCGCCACCACTACCGCTGCCTCCACGGACATGGAGACACAGACCGATCCCGCCGC AGCCGCAGCCGCAGCCGCCGCCGCGACCTCCTCGGCGGAGGTGCAGACGGACCCCTGGCTGCCGCCG GCGATGTCAGCTCCCCGCGCGCGTCGCGGGCGCAGGAAGTACGGCGCCGCCAACGCGCTCCTGCCCG AGTACGCCTTGCATCCTTCCATCGCGCCCACCCCCGGCTACCGAGGCTATACCTACCGCCCGCGAAG AGCCAAGGGTTCCACCCGCCGTCCCCGCCGACGCGCCGCCGCCACCACCCGCCGCCGCCGCCGCAGA CGCCAGCCCGCACTGGCTCCAGTCTCCGTGAGGAAAGTGGCGCGCGACGGACACACCCTGGTGCTGC CCAGGGCGCGCTACCACCCCAGCATCGTTTAAAAGCCTGTTGTGGTTCTTGCAGATATGGCCCTCACT TGCCGCCTCCGTTTCCCGGTGCCGGGATACCGAGGAGGAAGATCGCGCCGCAGGAGGGGTCTGGCCG GCCGCGGCCTGAGCGGAGGCAGCCGCCGCGCGCACCGGCGGCGACGCGCCACCAGCCGACGCATGC GCGGCGGGGTGCTGCCCCTGTTAATCCCCCTGATCGCCGCGGCGATCGGCGCCGTGCCCGGGATCGC CTCCGTGGCCTTGCAAGCGTCCCAGAGGCATTGACAGACTTGCAAACTTGCAAATATGGAAAAAAAA ACCCCAATAAAAAAGTCTAGACTCTCACGCTCGCTTGGTCCTGTGACTATTTTGTAGAATGGAAGAC ATCAACTTTGCGTCGCTGGCCCCGCGTCACGGCTCGCGCCCGTTCCTGGGACACTGGAACGATATCG GCACCAGCAACATGAGCGGTGGCGCCTTCAGTTGGGGCTCTCTGTGGAGCGGCATTAAAAGTATCGG GTCTGCCGTTAAAAATTACGGCTCCCGGGCCTGGAACAGCAGCACGGGCCAGATGTTGAGAGACAA GTTGAAAGAGCAGAACTTCCAGCAGAAGGTGGTGGAGGGCCTGGCCTCCGGCATCAACGGGGTGGT GGACCTGGCCAACCAGGCCGTGCAGAATAAGATCAACAGCAGACTGGACCCCCGGCCGCCGGTGGA GGAGGTGCCGCCGGCGCTGGAGACGGTGTCCCCCGATGGGCGTGGCGAGAAGCGCCCGCGGCCCGA TAGGGAAGAGACCACTCTGGTCACGCAGACCGATGAGCCGCCCCCGTATGAGGAGGCCCTGAAGCA AGGTCTGCCCACCACGCGGCCCATCGCGCCCATGGCCACCGGGGTGGTGGGCCGCCACACCCCCGCC ACGCTGGACTTGCCTCCGCCCGCCGATGTGCCGCAGCAGCAGAAGGCGGCACAGCCGGGCCCGCCCG CGACCGCCTCCCGTTCCTCCGCCGGTCCTCTGCGCCGCGCGGCCAGCGGCCCCCGCGGGGGGGTCGC GAGGCACGGCAACTGGCAGAGCACGCTGAACAGCATCGTGGGTCTGGGGGTGCGGTCCGTGAAGCG CCGCCGATGCTACTGAATAGCTTAGCTAACGTGTTGTATGTGTGTATGCGCCCTATGTCGCCGCCAGA GGAGCTGCTGAGTCGCCGCCGTTCGCGCGCCCACCACCACCGCCACTCCGCCCCTCAAGATGGCGAC CCCATCGATGATGCCGCAGTGGTCGTACATGCACATCTCGGGCCAGGACGCCTCGGAGTACCTGAGC CCCGGGCTGGTGCAGTTCGCCCGCGCCACCGAGAGCTACTTCAGCCTGAGTAACAAGTTTAGGAACC CCACGGTGGCGCCCACGCACGATGTGACCACCGACCGGTCTCAGCGCCTGACGCTGCGGTTCATTCC CGTGGACCGCGAGGACACCGCGTACTCGTACAAGGCGCGGTTCACCCTGGCCGTGGGCGACAACCGC GTGCTGGACATGGCCTCCACCTACTTTGACATCCGCGGGGTGCTGGACCGGGGTCCCACTTTCAAGCC CTACTCTGGCACCGCCTACAACTCCCTGGCCCCCAAGGGCGCTCCCAACTCCTGCGAGTGGGAGCAA GAGGAAACTCAGGCAGTTGAAGAAGCAGCAGAAGAGGAAGAAGAAGATGCTGACGGTCAAGCTGA GGAAGAGCAAGCAGCTACCAAAAAGACTCATGTATATGCTCAGGCTCCCCTTTCTGGCGAAAAAATT AGTAAAGATGGTCTGCAAATAGGAACGGACGCTACAGCTACAGAACAAAAACCTATTTATGCAGAC CCTACATTCCAGCCCGAACCCCAAATCGGGGAGTCCCAGTGGAATGAGGCAGATGCTACAGTCGCCG GCGGTAGAGTGCTAAAGAAATCTACTCCCATGAAACCATGCTATGGTTCCTATGCAAGACCCACAAA TGCTAATGGAGGTCAGGGTGTACTAACGGCAAATGCCCAGGGACAGCTAGAATCTCAGGTTGAAATG CAATTCTTTTCAACTTCTGAAAACGCCCGTAACGAGGCTAACAACATTCAGCCCAAATTGGTGCTGTA TAGTGAGGATGTGCACATGGAGACCCCGGATACGCACCTTTCTTACAAGCCCGCAAAAAGCGATGAC AATTCAAAAATCATGCTGGGTCAGCAGTCCATGCCCAACAGACCTAATTACATCGGCTTCAGAGACA ACTTTATCGGCCTCATGTATTACAATAGCACTGGCAACATGGGAGTGCTTGCAGGTCAGGCCTCTCAG TTGAATGCAGTGGTGGACTTGCAAGACAGAAACACAGAACTGTCCTACCAGCTCTTGCTTGATTCCA TGGGTGACAGAACCAGATACTTTTCCATGTGGAATCAGGCAGTGGACAGTTATGACCCAGATGTTAG AATTATTGAAAATCATGGAACTGAAGACGAGCTCCCCAACTATTGTTTCCCTCTGGGTGGCATAGGG GTAACTGACACTTACCAGGCTGTTAAAACCAACAATGGCAATAACGGGGGCCAGGTGACTTGGACA AAAGATGAAACTTTTGCAGATCGCAATGAAATAGGGGTGGGAAACAATTTCGCTATGGAGATCAACC TCAGTGCCAACCTGTGGAGAAACTTCCTGTACTCCAACGTGGCGCTGTACCTACCAGACAAGCTTAA GTACAACCCCTCCAATGTGGACATCTCTGACAACCCCAACACCTACGATTACATGAACAAGCGAGTG GTGGCCCCGGGGCTGGTGGACTGCTACATCAACCTGGGCGCGCGCTGGTCGCTGGACTACATGGACA ACGTCAACCCCTTCAACCACCACCGCAATGCGGGCCTGCGCTACCGCTCCATGCTCCTGGGCAACGG GCGCTACGTGCCCTTCCACATCCAGGTGCCCCAGAAGTTCTTTGCCATCAAGAACCTCCTCCTCCTGC CGGGCTCCTACACCTACGAGTGGAACTTCAGGAAGGATGTCAACATGGTCCTCCAGAGCTCTCTGGG TAACGATCTCAGGGTGGACGGGGCCAGCATCAAGTTCGAGAGCATCTGCCTCTACGCCACCTTCTTC CCCATGGCCCACAACACGGCCTCCACGCTCGAGGCCATGCTCAGGAACGACACCAACGACCAGTCCT TCAATGACTACCTCTCCGCCGCCAACATGCTCTACCCCATACCCGCCAACGCCACCAACGTCCCCATC TCCATCCCCTCGCGCAACTGGGCGGCCTTCCGCGGCTGGGCCTTCACCCGCCTCAAGACCAAGGAGA CCCCCTCCCTGGGCTCGGGATTCGACCCCTACTACACCTACTCGGGCTCCATTCCCTACCTGGACGGC ACCTTCTACCTCAACCACACTTTCAAGAAGGTCTCGGTCACCTTCGACTCCTCGGTCAGCTGGCCGGG CAACGACCGTCTGCTCACCCCCAACGAGTTCGAGATCAAGCGCTCGGTCGACGGGGAGGGCTACAAC GTGGCCCAGTGCAACATGACCAAGGACTGGTTCCTGGTCCAGATGCTGGCCAACTACAACATCGGCT ACCAGGGCTTCTACATCCCAGAGAGCTACAAGGACAGGATGTACTCCTTCTTCAGGAACTTCCAGCC CATGAGCCGGCAGGTGGTGGACCAGACCAAGTACAAGGACTACCAGGAGGTGGGCATCATCCACCA GCACAACAACTCGGGCTTCGTGGGCTACCTCGCCCCCACCATGCGCGAGGGACAGGCCTACCCCGCC AACTTCCCCTATCCGCTCATAGGCAAGACCGCGGTCGACAGCATCACCCAGAAAAAGTTCCTCTGCG ACCGCACCCTCTGGCGCATCCCCTTCTCCAGCAACTTCATGTCCATGGGTGCGCTCTCGGACCTGGGC CAGAACTTGCTCTACGCCAACTCCGCCCACGCCCTCGACATGACCTTCGAGGTCGACCCCATGGACG AGCCCACCCTTCTCTATGTTCTGTTCGAAGTCTTTGACGTGGTCCGGGTCCACCAGCCGCACCGCGGC GTCATCGAGACCGTGTACCTGCGTACGCCCTTCTCGGCCGGCAACGCCACCACCTAAAGAAGCAAGC CGCAGTCATCGCCGCCTGCATGCCGTCGGGTTCCACCGAGCAAGAGCTCAGGGCCATCGTCAGAGAC CTGGGATGCGGGCCCTATTTTTTGGGCACCTTCGACAAGCGCTTCCCTGGCTTTGTCTCCCCACACAA GCTGGCCTGCGCCATCGTCAACACGGCCGGCCGCGAGACCGGGGGCGTGCACTGGCTGGCCTTCGCC TGGAACCCGCGCTCCAAAACATGCTTCCTCTTTGACCCCTTCGGCTTTTCGGACCAGCGGCTCAAGCA AATCTACGAGTTCGAGTACGAGGGCTTGCTGCGTCGCAGCGCCATCGCCTCCTCGCCCGACCGCTGC GTCACCCTCGAAAAGTCCACCCAGACCGTGCAGGGGCCCGACTCGGCCGCCTGCGGTCTCTTCTGCT GCATGTTTCTGCACGCCTTTGTGCACTGGCCTCAGAGTCCCATGGACCGCAACCCCACCATGAACTTG CTGACGGGGGTGCCCAACTCCATGCTCCAGAGCCCCCAGGTCGAGCCCACCCTGCGCCGCAACCAGG AGCAGCTCTACAGCTTCCTGGAGCGCCACTCGCCTTACTTCCGCCGCCACAGCGCACAGATCAGGAG GGCCACCTCCTTCTGCCACTTGCAAGAGATGCAAGAAGGGTAATAACGATGTACACACTTTTTTTCTC AATAAATGGCATCTTTTTATTTATACAAGCTCTCTGGGGTATTCATTTCCCACCACCACCCGCCGTTGT CGCCATCTGGCTCTATTTAGAAATCGAAAGGGTTCTGCCGGGAGTCGCCGTGCGCCACGGGCAGGGA CACGTTGCGATACTGGTAGCGGGTGCCCCACTTGAACTCGGGCACCACCAGGCGAGGCAGCTCGGGG AAGTTTTCGCTCCACAGGCTGCGGGTCAGCACCAGCGCGTTCATCAGGTCGGGCGCCGAGATCTTGA AGTCGCAGTTGGGGCCGCCGCCCTGCGCGCGCGAGTTGCGGTACACCGGGTTGCAGCACTGGAACAC CAACAGCGCCGGGTGCTTCACGCTGGCCAGCACGCTGCGGTCGGAGATCAGCTCGGCGTCCAGGTCC TCCGCGTTGCTCAGCGCGAACGGGGTCATCTTGGGCACTTGCCGCCCCAGGAAGGGCGCGTGCCCCG GTTTCGAGTTGCAGTCGCAGCGCAGCGGGATCAGCAGGTGCCCGTGCCCGGACTCGGCGTTGGGGTA CAGCGCGCGCATGAAGGCCTGCATCTGGCGGAAGGCCATCTGGGCCTTGGCGCCCTCCGAGAAGAAC ATGCCGCAGGACTTGCCCGAGAACTGGTTTGCGGGGCAGCTGGCGTCGTGCAGGCAGCAGCGCGCGT CGGTGTTGGCGATCTGCACCACGTTGCGCCCCCACCGGTTCTTCACGATCTTGGCCTTGGACGATTGC TCCTTCAGCGCGCGCTGCCCGTTCTCGCTGGTCACATCCATCTCGATCACATGTTCCTTGTTCACCATG CTGCTGCCGTGCAGACACTTCAGCTCGCCCTCCGTCTCGGTGCAGCGGTGCTGCCACAGCGCGCAGC CCGTGGGCTCGAAAGACTTGTAGGTCACCTCCGCGAAGGACTGCAGGTACCCCTGCAAAAAGCGGCC CATCATGGTCACGAAGGTCTTGTTGCTGCTGAAGGTCAGCTGCAGCCCGCGGTGCTCCTCGTTCAGCC AGGTCTTGCACACGGCCGCCAGCGCCTCCACCTGGTCGGGCAGCATCTTGAAGTTCACCTTCAGCTCA TTCTCCACGTGGTACTTGTCCATCAGCGTGCGCGCCGCCTCCATGCCCTTCTCCCAGGCCGACACCAG CGGCAGGCTCACGGGGTTCTTCACCATCACCGTGGCCGCCGCCTCCGCCGCGCTTTCGCTTTCCGCCC CGCTGTTCTCTTCCTCTTCCTCCTCTTCCTCGCCGCCGCCCACTCGCAGCCCCCGCACCACGGGGTCGT CTTCCTGCAGGCGCTGCACCTTGCGCTTGCCGTTGCGCCCCTGCTTGATGCGCACGGGCGGGTTGCTG AAGCCCACCATCACCAGCGCGGCCTCTTCTTGCTCGTCCTCGCTGTCCAGAATGACCTCCGGGGAGG GGGGGTTGGTCATCCTCAGTACCGAGGCACGCTTCTTTTTCTTCCTGGGGGCGTTCGCCAGCTCCGCG GCTGCGGCCGCTGCCGAGGTCGAAGGCCGAGGGCTGGGCGTGCGCGGCACCAGCGCGTCCTGCGAG CCGTCCTCGTCCTCCTCGGACTCGAGACGGAGGCGGGCCCGCTTCTTCGGGGGCGCGCGGGGCGGCG GAGGCGGCGGCGGCGACGGAGACGGGGACGAGACATCGTCCAGGGTGGGTGGACGGCGGGCCGCG CCGCGTCCGCGCTCGGGGGTGGTCTCGCGCTGGTCCTCTTCCCGACTGGCCATCTCCCACTGCTCCTT CTCCTATAGGCAGAAAGAGATCATGGAGTCTCTCATGCGAGTCGAGAAGGAGGAGGACAGCCTAAC CGCCCCCTCTGAGCCCTCCACCACCGCCGCCACCACCGCCAATGCCGCCGCGGACGACGCGCCCACC GAGACCACCGCCAGTACCACCCTCCCCAGCGACGCACCCCCGCTCGAGAATGAAGTGCTGATCGAGC AGGACCCGGGTTTTGTGAGCGGAGAGGAGGATGAGGTGGATGAGAAGGAGAAGGAGGAGGTCGCC GCCTCAGTGCCAAAAGAGGATAAAAAGCAAGACCAGGACGACGCAGATAAGGATGAGACAGCAGT CGGGCGGGGGAACGGAAGCCATGATGCTGATGACGGCTACCTAGACGTGGGAGACGACGTGCTGCT TAAGCACCTGCACCGCCAGTGCGTCATCGTCTGCGACGCGCTGCAGGAGCGCTGCGAAGTGCCCCTG GACGTGGCGGAGGTCAGCCGCGCCTACGAGCGGCACCTCTTCGCGCCGCACGTGCCCCCCAAGCGCC GGGAGAACGGCACCTGCGAGCCCAACCCGCGTCTCAACTTCTACCCGGTCTTCGCGGTACCCGAGGT GCTGGCCACCTACCACATCTTTTTCCAAAACTGCAAGATCCCCCTCTCCTGCCGCGCCAACCGCACCC GCGCCGACAAAACCCTGACCCTGCGGCAGGGCGCCCACATACCTGATATCGCCTCTCTGGAGGAAGT GCCCAAGATCTTCGAGGGTCTCGGTCGCGACGAGAAACGGGCGGCGAACGCTCTGCACGGAGACAG CGAAAACGAGAGTCACTCGGGGGTGCTGGTGGAGCTCGAGGGCGACAACGCGCGCCTGGCCGTACT CAAGCGCAGCATAGAGGTCACCCACTTTGCCTACCCGGCGCTCAACCTGCCCCCCAAGGTCATGAGT GTGGTCATGGGCGAGCTCATCATGCGCCGCGCCCAGCCCCTGGCCGCGGATGCAAACTTGCAAGAGT CCTCCGAGGAAGGCCTGCCCGCGGTCAGCGACGAGCAGCTGGCGCGCTGGCTGGAGACCCGCGACC CCGCGCAGCTGGAGGAGCGGCGCAAGCTCATGATGGCCGCGGTGCTGGTCACCGTGGAGCTCGAGT GTCTGCAGCGCTTCTTCGCGGACCCCGAGATGCAGCGCAAGCTCGAGGAGACCCTGCACTACACCTT CCGCCAGGGCTACGTGCGCCAGGCCTGCAAGATCTCCAACGTGGAGCTCTGCAACCTGGTCTCCTAC CTGGGCATCCTGCACGAGAACCGCCTCGGGCAGAACGTCCTGCACTCCACCCTCAAAGGGGAGGCGC GCCGCGACTACATCCGCGACTGCGCCTACCTCTTCCTCTGCTACACCTGGCAGACGGCCATGGGGGTC TGGCAGCAGTGCCTGGAGGAGCGCAACCTCAAGGAGCTGGAAAAGCTCCTCAAGCGCACCCTCAGG GACCTCTGGACGGGCTTCAACGAGCGCTCGGTGGCCGCCGCGCTGGCGGACATCATCTTTCCCGAGC GCCTGCTCAAGACCCTGCAGCAGGGCCTGCCCGACTTCACCAGCCAGAGCATGCTGCAGAACTTCAG GACTTTCATCCTGGAGCGCTCGGGCATCCTGCCGGCCACTTGCTGCGCGCTGCCCAGCGACTTCGTGC CCATCAAGTACAGGGAGTGCCCGCCGCCGCTCTGGGGCCACTGCTACCTCTTCCAGCTGGCCAACTA CCTCGCCTACCACTCGGACCTCATGGAAGACGTGAGCGGCGAGGGCCTGCTCGAGTGCCACTGCCGC TGCAACCTCTGCACGCCCCACCGCTCTCTAGTCTGCAACCCGCAGCTGCTCAGCGAGAGTCAGATTAT CGGTACCTTCGAGCTGCAGGGTCCCTCGCCTGACGAGAAGTCCGCGGCTCCAGGGCTGAAACTCACT CCGGGGCTGTGGACTTCCGCCTACCTACGCAAATTTGTACCTGAGGACTACCACGCCCACGAGATCA GGTTCTACGAAGACCAATCCCGCCCGCCCAAGGCGGAGCTCACCGCCTGCGTCATCACCCAGGGGCA CATCCTGGGCCAATTGCAAGCCATCAACAAAGCCCGCCGAGAGTTCTTGCTGAAAAAGGGTCGGGGG GTGTACCTGGACCCCCAGTCCGGCGAGGAGCTAAACCCGCTACCCCCGCCGCCGCCCCAGCAGCGGG ACCTTGCTTCCCAGGATGGCACCCAGAAAGAAGCAGCAGCCGCCGCCGCCGCCGCAGCCATACATGC TTCTGGAGGAAGAGGAGGAGGACTGGGACAGTCAGGCAGAGGAGGTTTCGGACGAGGAGCAGGAG GAGATGATGGAAGACTGGGAGGAGGACAGCAGCCTAGACGAGGAAGCTTCAGAGGCCGAAGAGGT GGCAGACGCAACACCATCGCCCTCGGTCGCAGCCCCCTCGCCGGGGCCCCTGAAATCCTCCGAACCC AGCACCAGCGCTATAACCTCCGCTCCTCCGGCGCCGGCGCCACCCGCCCGCAGACCCAACCGTAGAT GGGACACCACAGGAACCGGGGTCGGTAAGTCCAAGTGCCCGCCGCCGCCACCGCAGCAGCAGCAGC AGCAGCGCCAGGGCTACCGCTCGTGGCGCGGGCACAAGAACGCCATAGTCGCCTGCTTGCAAGACTG CGGGGGCAACATCTCTTTCGCCCGCCGCTTCCTGCTATTCCACCACGGGGTCGCCTTTCCCCGCAATG TCCTGCATTACTACCGTCATCTCTACAGCCCCTACTGCAGCGGCGACCCAGAGGCGGCAGCGGCAGC CACAGCGGCGACCACCACCTAGGAAGATATCCTCCGCGGGCAAGACAGCGGCAGCAGCGGCCAGGA GACCCGCGGCAGCAGCGGCGGGAGCGGTGGGCGCACTGCGCCTCTCGCCCAACGAACCCCTCTCGAC CCGGGAGCTCAGACACAGGATCTTCCCCACTTTGTATGCCATCTTCCAACAGAGCAGAGGCCAGGAG CAGGAGCTGAAAATAAAAAACAGATCTCTGCGCTCCCTCACCCGCAGCTGTCTGTATCACAAAAGCG AAGATCAGCTTCGGCGCACGCTGGAGGACGCGGAGGCACTCTTCAGCAAATACTGCGCGCTCACTCT TAAAGACTAGCTCCGCGCCCTTCTCGAATTTAGGCGGGAGAAAACTACGTCATCGCCGGCCGCCGCC CAGCCCGCCCAGCCGAGATGAGCAAAGAGATTCCCACGCCATACATGTGGAGCTACCAGCCGCAGA TGGGACTCGCGGCGGGAGCGGCCCAGGACTACTCCACCCGCATGAACTACATGAGCGCGGGACCCC ACATGATCTCACAGGTCAACGGGATCCGCGCCCAGCGAAACCAAATACTGCTGGAACAGGCGGCCA TCACCGCCACGCCCCGCCATAATCTCAACCCCCGAAATTGGCCCGCCGCCCTCGTGTACCAGGAAAC CCCCTCCGCCACCACCGTACTACTTCCGCGTGACGCCCAGGCCGAAGTCCAGATGACTAACTCAGGG GCGCAGCTCGCGGGCGGCTTTCGTCACGGGGCGCGGCCGCTCCGACCAGGTATAAGACACCTGATGA TCAGAGGCCGAGGTATCCAGCTCAACGACGAGTCGGTGAGCTCTTCGCTCGGTCTCCGTCCGGACGG AACTTTCCAGCTCGCCGGATCCGGCCGCTCTTCGTTCACGCCCCGCCAGGCGTACCTGACTCTGCAGA CCTCGTCCTCGGAGCCCCGCTCCGGCGGCATCGGAACCCTCCAGTTCGTGGAGGAGTTCGTGCCCTCG GTCTACTTCAACCCCTTCTCGGGACCTCCCGGACGCTACCCCGACCAGTTCATTCCGAACTTTGACGC GGTGAAGGACTCGGCGGACGGCTACGACTGAATGTCAGGTGTCGAGGCAGAGCAGCTTCGCCTGAG ACACCTCGAGCACTGCCGCCGCCACAAGTGCTTCGCCCGCGGTTCTGGTGAGTTCTGCTACTTTCAGC TACCCGAGGAGCATACCGAGGGGCCGGCGCACGGCGTCCGCCTGACCACCCAGGGCGAGGTTACCT GTTCCCTCATCCGGGAGTTTACCCTCCGTCCCCTGCTAGTGGAGCGGGAGCGGGGTCCCTGTGTCCTA ACTATCGCCTGCAACTGCCCTAACCCTGGATTACATCAAGATCTTTGCTGTCATCTCTGTGCTGAGTTT AATAAACGCTGAGATCAGAATCTACTGGGGCTCCTGTCGCCATCCTGTGAACGCCACCGTCTTCACCC ACCCCGACCAGGCCCAGGCGAACCTCACCTGCGGTCTGCATCGGAGGGCCAAGAAGTACCTCACCTG GTACTTCAACGGCACCCCCTTTGTGGTTTACAACAGCTTCGACGGGGACGGAGTCTCCCTGAAAGAC CAGCTCTCCGGTCTCAGCTACTCCATCCACAAGAACACCACCCTCCAACTCTTCCCTCCCTACCTGCC GGGAACCTACGAGTGCGTCACCGGCCGCTGCACCCACCTCACCCGCCTGATCGTAAACCAGAGCTTT CCGGGAACAGATAACTCCCTCTTCCCCAGAACAGGAGGTGAGCTCAGGAAACTCCCCGGGGACCAG GGCGGAGACGTACCTTCGACCCTTGTGGGGTTAGGATTTTTTATTACCGGGTTGCTGGCTCTTTTAAT CAAAGTTTCCTTGAGATTTGTTCTTTCCTTCTACGTGTATGAACACCTCAACCTCCAATAACTCTACCC TTTCTTCGGAATCAGGTGACTTCTCTGAAATCGGGCTTGGTGTGCTGCTTACTCTGTTGATTTTTTTCC TTATCATACTCAGCCTTCTGTGCCTCAGGCTCGCCGCCTGCTGCGCACACATCTATATCTACTGCTGGT TGCTCAAGTGCAGGGGTCGCCACCCAAGATGAACAGGTACATGGTCCTATCGATCCTAGGCCTGCTG GCCCTGGCGGCCTGCAGCGCCGCCAAAAAAGAGATTACCTTTGAGGAGCCCGCTTGCAATGTAACTT TCAAGCCCGAGGGTGACCAATGCACCACCCTCGTCAAATGCGTTACCAATCATGAGAGGCTGCGCAT CGACTACAAAAACAAAACTGGCCAGTTTGCGGTCTATAGTGTGTTTACGCCCGGAGACCCCTCTAAC TACTCTGTCACCGTCTTCCAGGGCGGACAGTCTAAGATATTCAATTACACTTTCCCTTTTTATGAGTTA TGCGATGCGGTCATGTACATGTCAAAACAGTACAACCTGTGGCCTCCCTCTCCCCAGGCGTGTGTGG AAAATACTGGGTCTTACTGCTGTATGGCTTTCGCAATCACTACGCTCGCTCTAATCTGCACGGTGCTA TACATAAAATTCAGGCAGAGGCGAATCTTTATCGATGAAAAGAAAATGCCTTGATCGCTAACACCGG CTTTCTATCTGCAGAATGAATGCAATCACCTCCCTACTAATCACCACCACCCTCCTTGCGATTGCCCA TGGGTTGACACGAATCGAAGTGCCAGTGGGGTCCAATGTCACCATGGTGGGCCCCGCCGGCAATTCC ACCCTCATGTGGGAAAAATTTGTCCGCAATCAATGGGTTCATTTCTGCTCTAACCGAATCAGTATCAA GCCCAGAGCCATCTGCGATGGGCAAAATCTAACTCTGATCAATGTGCAAATGATGGATGCTGGGTAC TATTACGGGCAGCGGGGAGAAATCATTAATTACTGGCGACCCCACAAGGACTACATGCTGCATGTAG TCGAGGCACTTCCCACTACCACCCCCACTACCACCTCTCCCACCACCACCACCACTACTACTACTACT ACTACTACTACTACTACTACCACTACCGCTGCCCGCCATACCCGCAAAAGCACCATGATTAGCACAA AGCCCCCTCGTGCTCACTCCCACGCCGGCGGGCCCATCGGTGCGACCTCAGAAACCACCGAGCTTTG CTTCTGCCAATGCACTAACGCCAGCGCTCATGAACTGTTCGACCTGGAGAATGAGGATGTCCAGCAG AGCTCCGCTTGCCTGACCCAGGAGGCTGTGGAGCCCGTTGCCCTGAAGCAGATCGGTGATTCAATAA TTGACTCTTCTTCTTTTGCCACTCCCGAATACCCTCCCGATTCTACTTTCCACATCACGGGTACCAAAG ACCCTAACCTCTCTTTCTACCTGATGCTGCTGCTCTGTATCTCTGTGGTCTCTTCCGCGCTGATGTTAC TGGGGATGTTCTGCTGCCTGATCTGCCGCAGAAAGAGAAAAGCTCGCTCTCAGGGCCAACCACTGAT GCCCTTCCCCTACCCCCCGGATTTTGCAGATAACAAGATATGAGCTCGCTGCTGACACTAACCGCTTT ACTAGCCTGCGCTCTAACCCTTGTCGCTTGCGACTCGAGATTCCACAATGTCACAGCTGTGGCAGGAG AAAATGTTACTTTCAACTCCACGGCCGATACCCAGTGGTCGTGGAGTGGCTCAGGTAGCTACTTAACT ATCTGCAATAGCTCCACTTCCCCCGGCATATCCCCAACCAAGTACCAATGCAATGCCAGCCTGTTCAC CCTCATCAACGCTTCCACCCTGGACAATGGACTCTATGTAGGCTATGTACCCTTTGGTGGGCAAGGAA AGACCCACGCTTACAACCTGGAAGTTCGCCAGCCCAGAACCACTACCCAAGCTTCTCCCACCACCAC CACCACCACCACCATCACCAGCAGCAGCAGCAGCAGCAGCCACAGCAGCAGCAGCAGATTATTGAC TTTGGTTTTGGCCAGCTCATCTGCCGCTACCCAGGCCATCTACAGCTCTGTGCCCGAAACCACTCAGA TCCACCGCCCAGAAACGACCACCGCCACCACCCTACACACCTCCAGCGATCAGATGCCGACCAACAT CACCCCCTTGGCTCTTCAAATGGGACTTACAAGCCCCACTCCAAAACCAGTGGATGCGGCCGAGGTC TCCGCCCTCGTCAATGACTGGGCGGGGCTGGGAATGTGGTGGTTCGCCATAGGCATGATGGCGCTCT GCCTGCTTCTGCTCTGGCTCATCTGCTGCCTCCACCGCAGGCGAGCCAGACCCCCCATCTATAGACCC ATCATTGTCCTGAACCCCGATAATGATGGGATCCATAGATTGGATGGCCTGAAAAACCTACTTTTTTC TTTTACAGTATGATAAATTGAGACATGCCTCGCATTTTCTTGTACATGTTCCTTCTCCCACCTTTTCTG GGGTGTTCTACGCTGGCCGCTGTGTCTCACCTGGAGGTAGACTGCCTCTCACCCTTCACTGTCTACCT GCTTTACGGATTGGTCACCCTCACTCTCATCTGCAGCCTAATCACAGTAATCATCGCCTTCATCCAGT GCATTGATTACATCTGTGTGCGCCTCGCATACTTCAGACACCACCCGCAGTACCGAGACAGGAACAT TGCCCAACTTCTAAGACTGCTCTAATCATGCATAAGACTGTGATCTGCCTTCTGATCCTCTGCATCCT GCCCACCCTCACCTCCTGCCAGTACACCACAAAATCTCCGCGCAAAAGACATGCCTCCTGCCGCTTCA CCCAACTGTGGAATATACCCAAATGCTACAACGAAAAGAGCGAGCTCTCCGAAGCTTGGCTGTATGG GGTCATCTGTGTCTTAGTTTTCTGCAGCACTGTCTTTGCCCTCATAATCTACCCCTACTTTGATTTGGG ATGGAACGCGATCGATGCCATGAATTACCCCACCTTTCCCGCACCCGAGATAATTCCACTGCGACAA GTTGTACCCGTTGTCGTTAATCAACGCCCCCCATCCCCTACGCCCACTGAAATCAGCTACTTTAACCT AACAGGCGGAGATGACTGACGCCCTAGATCTAGAAATGGACGGCATCAGTACCGAGCAGCGTCTCCT AGAGAGGCGCAGGCAGGCGGCTGAGCAAGAGCGCCTCAATCAGGAGCTCCGAGATCTCGTTAACCT GCACCAGTGCAAAAGAGGCATCTTTTGTCTGGTAAAGCAGGCCAAAGTCACCTACGAGAAGACCGG CAACAGCCACCGCCTCAGTTACAAATTGCCCACCCAGCGCCAGAAGCTGGTGCTCATGGTGGGTGAG AATCCCATCACCGTCACCCAGCACTCGGTAGAGACCGAGGGGTGTCTGCACTCCCCCTGTCGGGGTC CAGAAGACCTCTGCACCCTGGTAAAGACCCTGTGCGGTCTCAGAGATTTAGTCCCCTTTAACTAATCA AACACTGGAATCAATAAAAAGAATCACTTACTTAAAATCAGACAGCAGGTCTCTGTCCAGTTTATTC AGCAGCACCTCCTTCCCCTCCTCCCAACTCTGGTACTCCAAACGCCTTCTGGCGGCAAACTTCCTCCA CACCCTGAAGGGAATGTCAGATTCTTGCTCCTGTCCCTCCGCACCCACTATCTTCATGTTGTTGCAGA TGAAGCGCACCAAAACGTCTGACGAGAGCTTCAACCCCGTGTACCCCTATGACACGGAAAGCGGCCC TCCCTCCGTCCCTTTCCTCACCCCTCCCTTCGTGTCTCCCGATGGATTCCAAGAAAGTCCCCCCGGGGT CCTGTCTCTGAACCTGGCCGAGCCCCTGGTCACTTCCCACGGCATGCTCGCCCTGAAAATGGGAAGT GGCCTCTCCCTGGACGACGCTGGCAACCTCACCTCTCAAGATATCACCACCGCTAGCCCTCCCCTCAA AAAAACCAAGACCAACCTCAGCCTAGAAACCTCATCCCCCCTAACTGTGAGCACCTCAGGCGCCCTC ACCGTAGCAGCCGCCGCTCCCCTGGCGGTGGCCGGCACCTCCCTCACCATGCAATCAGAGGCCCCCC TGACAGTACAGGATGCAAAACTCACCCTGGCCACCAAAGGCCCCCTGACCGTGTCTGAAGGCAAACT GGCCTTGCAAACATCGGCCCCGCTGACGGCCGCTGACAGCAGCACCCTCACAGTCAGTGCCACACCA CCCCTTAGCACAAGCAATGGCAGCTTGGGTATTGACATGCAAGCCCCCATTTACACCACCAATGGAA AACTAGGACTTAACTTTGGCGCTCCCCTGCATGTGGTAGACAGCCTAAATGCACTGACTGTAGTTACT GGCCAAGGTCTTACGATAAACGGAACAGCCCTACAAACTAGAGTCTCAGGTGCCCTCAACTATGACA CATCAGGAAACCTAGAATTGAGAGCTGCAGGGGGTATGCGAGTTGATGCAAATGGTCAACTTATCCT TGATGTAGCTTACCCATTTGATGCACAAAACAATCTCAGCCTTAGGCTTGGACAGGGACCCCTGTTTG TTAACTCTGCCCACAACTTGGATGTTAACTACAACAGAGGCCTCTACCTGTTCACATCTGGAAATACC AAAAAGCTAGAAGTTAATATCAAAACAGCCAAGGGTCTCATTTATGATGACACTGCTATAGCAATCA ATGCGGGTGATGGGCTACAGTTTGACTCAGGCTCAGATACAAATCCATTAAAAACTAAACTTGGATT AGGACTGGATTATGACTCCAGCAGAGCCATAATTGCTAAACTGGGAACTGGCCTAAGCTTTGACAAC ACAGGTGCCATCACAGTAGGCAACAAAAATGATGACAAGCTTACCTTGTGGACCACACCAGACCCAT CCCCTAACTGTAGAATCTATTCAGAGAAAGATGCTAAATTCACACTTGTTTTGACTAAATGCGGCAGT CAGGTGTTGGCCAGCGTTTCTGTTTTATCTGTAAAAGGTAGCCTTGCGCCCATCAGTGGCACAGTAAC TAGTGCTCAGATTGTCCTCAGATTTGATGAAAATGGAGTTCTACTAAGCAATTCTTCCCTTGACCCTC AATACTGGAACTACAGAAAAGGTGACCTTACAGAGGGCACTGCATATACCAACGCAGTGGGATTTAT GCCCAACCTCACAGCATACCCAAAAACACAGAGCCAAACTGCTAAAAGCAACATTGTAAGTCAGGTT TACTTGAATGGGGACAAATCCAAACCCATGACCCTCACCATTACCCTCAATGGAACTAATGAAACAG GAGATGCCACAGTAAGCACTTACTCCATGTCATTCTCATGGAACTGGAATGGAAGTAATTACATTAA TGAAACGTTCCAAACCAACTCCTTCACCTTCTCCTACATCGCCCAAGAATAAAAAGCATGACGCTGTT GATTTGATTCAATGTGTTTCTGTTTTATTTTCAAGCACAACAAAATCATTCAAGTCATTCTTCCATCTT AGCTTAATAGACACAGTAGCTTAATAGACCCAGTAGTGCAAAGCCCCATTCTAGCTTATAACTAGTG GAGAAGTACTCGCCTACATGGGGGTAGAGTCATAATCGTGCATCAGGATAGGGCGGTGGTGCTGCAG CAGCGCGCGAATAAACTGCTGCCGCCGCCGCTCCGTCCTGCAGGAATACAACATGGCAGTGGTCTCC TCAGCGATGATTCGCACCGCCCGCAGCATAAGGCGCCTTGTCCTCCGGGCACAGCAGCGCACCCTGA TCTCACTTAAATCAGCACAGTAACTGCAGCACAGCACCACAATATTGTTCAAAATCCCACAGTGCAA GGCGCTGTATCCAAAGCTCATGGCGGGGACCACAGAACCCACGTGGCCATCATACCACAAGCGCAG GTAGATTAAGTGGCGACCCCTCATAAACACGCTGGACATAAACATTACCTCTTTTGGCATGTTGTAAT TCACCACCTCCCGGTACCATATAAACCTCTGATTAAACATGGCGCCATCCACCACCATCCTAAACCAG CTGGCCAAAACCTGCCCGCCGGCTATACACTGCAGGGAACCGGGACTGGAACAATGACAGTGGAGA GCCCAGGACTCGTAACCATGGATCATCATGCTCGTCATGATATCAATGTTGGCACAACACAGGCACA CGTGCATACACTTCCTCAGGATTACAAGCTCCTCCCGCGTTAGAACCATATCCCAGGGAACAACCCA TTCCTGAATCAGCGTAAATCCCACACTGCAGGGAAGACCTCGCACGTAACTCACGTTGTGCATTGTC AAAGTGTTACATTCGGGCAGCAGCGGATGATCCTCCAGTATGGTAGCGCGGGTTTCTGTCTCAAAAG GAGGTAGACGATCCCTACTGTACGGAGTGCGCCGAGACAACCGAGATCGTGTTGGTCGTAGTGTCAT GCCAAATGGAACGCCGGACGTAGTCATATTTCCTGAAGTCTTAGATCTCTCAACGCAGCACCAGCAC CAACACTTCGCAGTGTAAAAGGCCAAGTGCCGAGAGAGTATATATAGGAATAAAAAGTGACGTAAA CGGGCAAAGTCCAAAAAACGCCCAGAAAAACCGCACGCGAACCTACGCCCCGAAACGAAAGCCAAA AAACACTAGACACTCCCTTCCGGCGTCAACTTCCGCTTTCCCACGCTACGTCACTTGCCCCAGTCAAA CAAACTACATATCCCGAACTTCCAAGTCGCCACGCCCAAAACACCGCCTACACCTCCCCGCCCGCCG GCCCGCCCCCAAACCCGCCTCCCGCCCCGCGCCCCGCCCCGCGCCGCCCATCTCATTATCATATTGGC TTCAATCCAAAATAAGGTATATTATTGATGATGGTTTAAACGGATCCTCTAGAGTCGACCTGCAGGC ATGCAAGCTTGAGTATTCTATAGTGTCACCTAAATAGCTTGGCGTAATCATGGTCATAGCTGTTTCCT GTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCT GGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGA AACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGAACCCCTTGCGGCCGCCCGGGCCGTCG ACCAATTCTCATGTTTGACAGCTTATCATCGAATTTCTGCCATTCATCCGCTTATTATCACTTATTCAG GCGTAGCAACCAGGCGTTTAAGGGCACCAATAACTGCCTTAAAAAAATTACGCCCCGCCCTGCCACT CATCGCAGTACTGTTGTAATTCATTAAGCATTCTGCCGACATGGAAGCCATCACAAACGGCATGATG AACCTGAATCGCCAGCGGCATCAGCACCTTGTCGCCTTGCGTATAATATTTGCCCATGGTGAAAACG GGGGCGAAGAAGTTGTCCATATTGGCCACGTTTAAATCAAAACTGGTGAAACTCACCCAGGGATTGG CTGAGACGAAAAACATATTCTCAATAAACCCTTTAGGGAAATAGGCCAGGTTTTCACCGTAACACGC CACATCTTGCGAATATATGTGTAGAAACTGCCGGAAATCGTCGTGGTATTCACTCCAGAGCGATGAA AACGTTTCAGTTTGCTCATGGAAAACGGTGTAACAAGGGTGAACACTATCCCATATCACCAGCTCAC CGTCTTTCATTGCCATACGGAATTCCGGATGAGCATTCATCAGGCGGGCAAGAATGTGAATAAAGGC CGGATAAAACTTGTGCTTATTTTTCTTTACGGTCTTTAAAAAGGCCGTAATATCCAGCTGAACGGTCT GGTTATAGGTACATTGAGCAACTGACTGAAATGCCTCAAAATGTTCTTTACGATGCCATTGGGATATA TCAACGGTGGTATATCCAGTGATTTTTTTCTCCATTTTAGCTTCCTTAGCTCCTGAAAATCTCGATAAC TCAAAAAATACGCCCGGTAGTGATCTTATTTCATTATGGTGAAAGTTGGAACCTCTTACGTGCCGATC AACGTCTCATTTTCGCCAAAAGTTGGCCCAGGGCTTCCCGGTATCAACAGGGACACCAGGATTTATTT ATTCTGCGAAGTGATCTTCCGTCACAGGTATTTATTCGCGATAAGCTCATGGAGCGGCGTAACCGTCG CACAGGAAGGACAGAGAAAGCGCGGATCTGGGAAGTGACGGACAGAACGGTCAGGACCTGGATTG GGGAGGCGGTTGCCGCCGCTGCTGCTGACGGTGTGACGTTCTCTGTTCCGGTCACACCACATACGTTC CGCCATTCCTATGCGATGCACATGCTGTATGCCGGTATACCGCTGAAAGTTCTGCAAAGCCTGATGG GACATAAGTCCATCAGTTCAACGGAAGTCTACACGAAGGTTTTTGCGCTGGATGTGGCTGCCCGGCA CCGGGTGCAGTTTGCGATGCCGGAGTCTGATGCGGTTGCGATGCTGAAACAATTATCCTGAGAATAA ATGCCTTGGCCTTTATATGGAAATGTGGAACTGAGTGGATATGCTGTTTTTGTCTGTTAAACAGAGAA GCTGGCTGTTATCCACTGAGAAGCGAACGAAACAGTCGGGAAAATCTCCCATTATCGTAGAGATCCG CATTATTAATCTCAGGAGCCTGTGTAGCGTTTATAGGAAGTAGTGTTCTGTCATGATGCCTGCAAGCG GTAACGAAAACGATTTGAATATGCCTTCAGGAACAATAGAAATCTTCGTGCGGTGTTACGTTGAAGT GGAGCGGATTATGTCAGCAATGGACAGAACAACCTAATGAACACAGAACCATGATGTGGTCTGTCCT TTTACAGCCAGTAGTGCTCGCCGCAGTCGAGCGACAGGGCGAAGCCCTCGAGTGAGCGAGGAAGCA CCAGGGAACAGCACTTATATATTCTGCTTACACACGATGCCTGAAAAAACTTCCCTTGGGGTTATCCA CTTATCCACGGGGATATTTTTATAATTATTTTTTTTATAGTTTTTAGATCTTCTTTTTTAGAGCGCCTTG TAGGCCTTTATCCATGCTGGTTCTAGAGAAGGTGTTGTGACAAATTGCCCTTTCAGTGTGACAAATCA CCCTCAAATGACAGTCCTGTCTGTGACAAATTGCCCTTAACCCTGTGACAAATTGCCCTCAGAAGAA GCTGTTTTTTCACAAAGTTATCCCTGCTTATTGACTCTTTTTTATTTAGTGTGACAATCTAAAAACTTG TCACACTTCACATGGATCTGTCATGGCGGAAACAGCGGTTATCAATCACAAGAAACGTAAAAATAGC CCGCGAATCGTCCAGTCAAACGACCTCACTGAGGCGGCATATAGTCTCTCCCGGGATCAAAAACGTA TGCTGTATCTGTTCGTTGACCAGATCAGAAAATCTGATGGCACCCTACAGGAACATGACGGTATCTG CGAGATCCATGTTGCTAAATATGCTGAAATATTCGGATTGACCTCTGCGGAAGCCAGTAAGGATATA CGGCAGGCATTGAAGAGTTTCGCGGGGAAGGAAGTGGTTTTTTATCGCCCTGAAGAGGATGCCGGCG ATGAAAAAGGCTATGAATCTTTTCCTTGGTTTATCAAACGTGCGCACAGTCCATCCAGAGGGCTTTAC AGTGTACATATCAACCCATATCTCATTCCCTTCTTTATCGGGTTACAGAACCGGTTTACGCAGTTTCG GCTTAGTGAAACAAAAGAAATCACCAATCCGTATGCCATGCGTTTATACGAATCCCTGTGTCAGTAT CGTAAGCCGGATGGCTCAGGCATCGTCTCTCTGAAAATCGACTGGATCATAGAGCGTTACCAGCTGC CTCAAAGTTACCAGCGTATGCCTGACTTCCGCCGCCGCTTCCTGCAGGTCTGTGTTAATGAGATCAAC AGCAGAACTCCAATGCGCCTCTCATACATTGAGAAAAAGAAAGGCCGCCAGACGACTCATATCGTAT TTTCCTTCCGCGATATCACTTCCATGACGACAGGATAGTCTGAGGGTTATCTGTCACAGATTTGAGGG TGGTTCGTCACATTTGTTCTGACCTACTGAGGGTAATTTGTCACAGTTTTGCTGTTTCCTTCAGCCTGC ATGGATTTTCTCATACTTTTTGAACTGTAATTTTTAAGGAAGCCAAATTTGAGGGCAGTTTGTCACAG TTGATTTCCTTCTCTTTCCCTTCGTCATGTGACCTGATATCGGGGGTTAGTTCGTCATCATTGATGAGG GTTGATTATCACAGTTTATTACTCTGAATTGGCTATCCGCGTGTGTACCTCTACCTGGAGTTTTTCCCA CGGTGGATATTTCTTCTTGCGCTGAGCGTAAGAGCTATCTGACAGAACAGTTCTTCTTTGCTTCCTCG CCAGTTCGCTCGCTATGCTCGGTTACACGGCTGCGGCGAGCGCTAGTGATAATAAGTGACTGAGGTA TGTGCTCTTCTTATCTCCTTTTGTAGTGTTGCTCTTATTTTAAACAACTTTGCGGTTTTTTGATGACTTT GCGATTTTGTTGTTGCTTTGCAGTAAATTGCAAGATTTAATAAAAAAACGCAAAGCAATGATTAAAG GATGTTCAGAATGAAACTCATGGAAACACTTAACCAGTGCATAAACGCTGGTCATGAAATGACGAAG GCTATCGCCATTGCACAGTTTAATGATGACAGCCCGGAAGCGAGGAAAATAACCCGGCGCTGGAGA ATAGGTGAAGCAGCGGATTTAGTTGGGGTTTCTTCTCAGGCTATCAGAGATGCCGAGAAAGCAGGGC GACTACCGCACCCGGATATGGAAATTCGAGGACGGGTTGAGCAACGTGTTGGTTATACAATTGAACA AATTAATCATATGCGTGATGTGTTTGGTACGCGATTGCGACGTGCTGAAGACGTATTTCCACCGGTGA TCGGGGTTGCTGCCCATAAAGGTGGCGTTTACAAAACCTCAGTTTCTGTTCATCTTGCTCAGGATCTG GCTCTGAAGGGGCTACGTGTTTTGCTCGTGGAAGGTAACGACCCCCAGGGAACAGCCTCAATGTATC ACGGATGGGTACCAGATCTTCATATTCATGCAGAAGACACTCTCCTGCCTTTCTATCTTGGGGAAAAG GACGATGTCACTTATGCAATAAAGCCCACTTGCTGGCCGGGGCTTGACATTATTCCTTCCTGTCTGGC TCTGCACCGTATTGAAACTGAGTTAATGGGCAAATTTGATGAAGGTAAACTGCCCACCGATCCACAC CTGATGCTCCGACTGGCCATTGAAACTGTTGCTCATGACTATGATGTCATAGTTATTGACAGCGCGCC TAACCTGGGTATCGGCACGATTAATGTCGTATGTGCTGCTGATGTGCTGATTGTTCCCACGCCTGCTG AGTTGTTTGACTACACCTCCGCACTGCAGTTTTTCGATATGCTTCGTGATCTGCTCAAGAACGTTGAT CTTAAAGGGTTCGAGCCTGATGTACGTATTTTGCTTACCAAATACAGCAATAGTAATGGCTCTCAGTC CCCGTGGATGGAGGAGCAAATTCGGGATGCCTGGGGAAGCATGGTTCTAAAAAATGTTGTACGTGAA ACGGATGAAGTTGGTAAAGGTCAGATCCGGATGAGAACTGTTTTTGAACAGGCCATTGATCAACGCT CTTCAACTGGTGCCTGGAGAAATGCTCTTTCTATTTGGGAACCTGTCTGCAATGAAATTTTCGATCGT CTGATTAAACCACGCTGGGAGATTAGATAATGAAGCGTGCGCCTGTTATTCCAAAACATACGCTCAA TACTCAACCGGTTGAAGATACTTCGTTATCGACACCAGCTGCCCCGATGGTGGATTCGTTAATTGCGC GCGTAGGAGTAATGGCTCGCGGTAATGCCATTACTTTGCCTGTATGTGGTCGGGATGTGAAGTTTACT CTTGAAGTGCTCCGGGGTGATAGTGTTGAGAAGACCTCTCGGGTATGGTCAGGTAATGAACGTGACC AGGAGCTGCTTACTGAGGACGCACTGGATGATCTCATCCCTTCTTTTCTACTGACTGGTCAACAGACA CCGGCGTTCGGTCGAAGAGTATCTGGTGTCATAGAAATTGCCGATGGGAGTCGCCGTCGTAAAGCTG CTGCACTTACCGAAAGTGATTATCGTGTTCTGGTTGGCGAGCTGGATGATGAGCAGATGGCTGCATT ATCCAGATTGGGTAACGATTATCGCCCAACAAGTGCTTATGAACGTGGTCAGCGTTATGCAAGCCGA TTGCAGAATGAATTTGCTGGAAATATTTCTGCGCTGGCTGATGCGGAAAATATTTCACGTAAGATTAT TACCCGCTGTATCAACACCGCCAAATTGCCTAAATCAGTTGTTGCTCTTTTTTCTCACCCCGGTGAACT ATCTGCCCGGTCAGGTGATGCACTTCAAAAAGCCTTTACAGATAAAGAGGAATTACTTAAGCAGCAG GCATCTAACCTTCATGAGCAGAAAAAAGCTGGGGTGATATTTGAAGCTGAAGAAGTTATCACTCTTT TAACTTCTGTGCTTAAAACGTCATCTGCATCAAGAACTAGTTTAAGCTCACGACATCAGTTTGCTCCT GGAGCGACAGTATTGTATAAGGGCGATAAAATGGTGCTTAACCTGGACAGGTCTCGTGTTCCAACTG AGTGTATAGAGAAAATTGAGGCCATTCTTAAGGAACTTGAAAAGCCAGCACCCTGATGCGACCACGT TTTAGTCTACGTTTATCTGTCTTTACTTAATGTCCTTTGTTACAGGCCAGAAAGCATAACTGGCCTGAA TATTCTCTCTGGGCCCACTGTTCCACTTGTATCGTCGGTCTGATAATCAGACTGGGACCACGGTCCCA CTCGTATCGTCGGTCTGATTATTAGTCTGGGACCACGGTCCCACTCGTATCGTCGGTCTGATTATTAG TCTGGGACCACGGTCCCACTCGTATCGTCGGTCTGATAATCAGACTGGGACCACGGTCCCACTCGTAT CGTCGGTCTGATTATTAGTCTGGGACCATGGTCCCACTCGTATCGTCGGTCTGATTATTAGTCTGGGA CCACGGTCCCACTCGTATCGTCGGTCTGATTATTAGTCTGGAACCACGGTCCCACTCGTATCGTCGGT CTGATTATTAGTCTGGGACCACGGTCCCACTCGTATCGTCGGTCTGATTATTAGTCTGGGACCACGAT CCCACTCGTGTTGTCGGTCTGATTATCGGTCTGGGACCACGGTCCCACTTGTATTGTCGATCAGACTA TCAGCGTGAGACTACGATTCCATCAATGCCTGTCAAGGGCAAGTATTGACATGTCGTCGTAACCTGT AGAACGGAGTAACCTCGGTGTGCGGTTGTATGCCTGCTGTGGATTGCTGCTGTGTCCTGCTTATCCAC AACATTTTGCGCACGGTTATGTGGACAAAATACCTGGTTACCCAGGCCGTGCCGGCACGTTAACCGG GCTGCATCCGATGCAAGTGTGTCGCTGTCGACGAGCTCGCGAGCTCGGACATGAGGTTGCCCCGTAT TCAGTGTCGCTGATTTGTATTGTCTGAAGTTGTTTTTACGTTAAGTTGATGCAGATCAATTAATACGAT ACCTGCGTCATAATTGATTATTTGACGTGGTTTGATGGCCTCCACGCACGTTGTGATATGTAGATGAT AATCATTATCACTTTACGGGTCCTTTCCGGTGATCCGACAGGTTACGGGGCGGCGACCTCGCGGGTTT TCGCTATTTATGAAAATTTTCCGGTTTAAGGCGTTTCCGTTCTTCTTCGTCATAACTTAATGTTTTTATT TAAAATACCCTCTGAAAAGAAAGGAAACGACAGGTGCTGAAAGCGAGCTTTTTGGCCTCTGTCGTTT CCTTTCTCTGTTTTTGTCCGTGGAATGAACAATGGAAGTCCGAGCTCATCGCTAATAACTTCGTATAG CATACATTATACGAAGTTATATTCGATGCGGCCGCAAGGGGTTCGCGTCAGCGGGTGTTGGCGGGTG TCGGGGCTGGCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAA ATACCGCACAGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACT GTTGGGAAGGGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGC AAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAA TTGTAATACGACTCACTATAGGGCGAATTCGAGCTCGGTACCCGGGGATCCTCGTTTAAAC Polynucleotide sequence encoding ChAd155#1375 backbone construct SEQ ID NO: 9 CATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAATGAGATGGGCGGCGCGGGGCG GGGCGCGGGGCGGGAGGCGGGTTTGGGGGCGGGCCGGCGGGCGGGGCGGTGTGGCGGAAGTGGAC TTTGTAAGTGTGGCGGATGTGACTTGCTAGTGCCGGGCGCGGTAAAAGTGACGTTTTCCGTGCGCGA CAACGCCCCCGGGAAGTGACATTTTTCCCGCGGTTTTTACCGGATGTTGTAGTGAATTTGGGCGTAAC CAAGTAAGATTTGGCCATTTTCGCGGGAAAACTGAAACGGGGAAGTGAAATCTGATTAATTTTGCGT TAGTCATACCGCGTAATATTTGTCTAGGGCCGAGGGACTTTGGCCGATTACGTGGAGGACTCGCCCA GGTGTTTTTTGAGGTGAATTTCCGCGTTCCGGGTCAAAGTCTGCGTTTTATTATTATAGGATATCCCAT TGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTT GACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATG GAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGT GGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCT ATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCC TACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCA ATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAG TTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAA TGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCTCCCTATCAGTGATAGAGATCT CCCTATCAGTGATAGAGATCGTCGACGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCAT CCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGCGGCCGGGAACGGTGCA TTGGAACGCGGATTCCCCGTGCCAAGAGTGAGATCTTCCGTTTATCTAGGTACCGGGCCCCCCCTCGA GGTCGACGGTATCGATAAGCTTCACGCTGCCGCAAGCACTCAGGGCGCAAGGGCTGCTAAAGGAAG CGGAACACGTAGAAAGCCAGTCCGCAGAAACGGTGCTGACCCCGGATGAATGTCAGCTACTGGGCT ATCTGGACAAGGGAAAACGCAAGCGCAAAGAGAAAGCAGGTAGCTTGCAGTGGGCTTACATGGCGA TAGCTAGACTGGGCGGTTTTATGGACAGCAAGCGAACCGGAATTGCCAGCTGGGGCGCCCTCTGGTA AGGTTGGGAAGCCCTGCAAAGTAAACTGGATGGCTTTCTTGCCGCCAAGGATCTGATGGCGCAGGGG ATCAAGATCTAACCAGGAGCTATTTAATGGCAACAGTTAACCAGCTGGTACGCAAACCACGTGCTCG CAAAGTTGCGAAAAGCAACGTGCCTGCGCTGGAAGCATGCCCGCAAAAACGTGGCGTATGTACTCGT GTATATACTACCACTCCTAAAAAACCGAACTCCGCGCTGCGTAAAGTATGCCGTGTTCGTCTGACTAA CGGTTTCGAAGTGACTTCCTACATCGGTGGTGAAGGTCACAACCTGCAGGAGCACTCCGTGATCCTG ATCCGTGGCGGTCGTGTTAAAGACCTCCCGGGTGTTCGTTACCACACCGTACGTGGTGCGCTTGACTG CTCCGGCGTTAAAGACCGTAAGCAGGCTCGTTCCAAGTATGGCGTGAAGCGTCCTAAGGCTTAATGG TAGATCTGATCAAGAGACAGGATGACGGTCGTTTCGCATGCTTGAACAAGATGGATTGCACGCAGGT TCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTG ATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGT GCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCG CAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCA GGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGC TGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACG TACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCA GCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCG ATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTG GGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCG AATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTAT CGCCTTCTTGACGAGTTCTTCTGAGCGGGACTCTGGGGTTCGAAATGACCGACCAAGCGACGCCCAA CCTGCCATCACGAGATTTCGATTCCACCGCCGCCTTCTATGAAAGGTTGGGCTTCGGAATCGTTTTCC GGGACGCCGGCTGGATGATCCTCCAGCGCGGGGATCTCATGCTGGAGTTCTTCGCCCACCCCGGGCT CGATCCCCTCGGGGGGAATCAGAATTCAGTCGACAGCGGCCGCGATCTGCTGTGCCTTCTAGTTGCC AGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTT CCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGT GGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCT CTATGGCCGATCAGCGATCGCTGAGGTGGGTGAGTGGGCGTGGCCTGGGGTGGTCATGAAAATATAT AAGTTGGGGGTCTTAGGGTCTCTTTATTTGTGTTGCAGAGACCGCCGGAGCCATGAGCGGGAGCAGC AGCAGCAGCAGTAGCAGCAGCGCCTTGGATGGCAGCATCGTGAGCCCTTATTTGACGACGCGGATGC CCCACTGGGCCGGGGTGCGTCAGAATGTGATGGGCTCCAGCATCGACGGCCGACCCGTCCTGCCCGC AAATTCCGCCACGCTGACCTATGCGACCGTCGCGGGGACGCCGTTGGACGCCACCGCCGCCGCCGCC GCCACCGCAGCCGCCTCGGCCGTGCGCAGCCTGGCCACGGACTTTGCATTCCTGGGACCACTGGCGA CAGGGGCTACTTCTCGGGCCGCTGCTGCCGCCGTTCGCGATGACAAGCTGACCGCCCTGCTGGCGCA GTTGGATGCGCTTACTCGGGAACTGGGTGACCTTTCTCAGCAGGTCATGGCCCTGCGCCAGCAGGTCT CCTCCCTGCAAGCTGGCGGGAATGCTTCTCCCACAAATGCCGTTTAAGATAAATAAAACCAGACTCT GTTTGGATTAAAGAAAAGTAGCAAGTGCATTGCTCTCTTTATTTCATAATTTTCCGCGCGCGATAGGC CCTAGACCAGCGTTCTCGGTCGTTGAGGGTGCGGTGTATCTTCTCCAGGACGTGGTAGAGGTGGCTCT GGACGTTGAGATACATGGGCATGAGCCCGTCCCGGGGGTGGAGGTAGCACCACTGCAGAGCTTCATG CTCCGGGGTGGTGTTGTAGATGATCCAGTCGTAGCAGGAGCGCTGGGCATGGTGCCTAAAAATGTCC TTCAGCAGCAGGCCGATGGCCAGGGGGAGGCCCTTGGTGTAAGTGTTTACAAAACGGTTAAGTTGGG AAGGGTGCATTCGGGGAGAGATGATGTGCATCTTGGACTGTATTTTTAGATTGGCGATGTTTCCGCCC AGATCCCTTCTGGGATTCATGTTGTGCAGGACCACCAGTACAGTGTATCCGGTGCACTTGGGGAATTT GTCATGCAGCTTAGAGGGAAAAGCGTGGAAGAACTTGGAGACGCCTTTGTGGCCTCCCAGATTTTCC ATGCATTCGTCCATGATGATGGCAATGGGCCCGCGGGAGGCAGCTTGGGCAAAGATATTTCTGGGGT CGCTGACGTCGTAGTTGTGTTCCAGGGTGAGGTCGTCATAGGCCATTTTTACAAAGCGCGGGCGGAG GGTGCCCGACTGGGGGATGATGGTCCCCTCTGGCCCTGGGGCGTAGTTGCCCTCGCAGATCTGCATTT CCCAGGCCTTAATCTCGGAGGGGGGAATCATATCCACCTGCGGGGCGATGAAGAAAACGGTTTCCGG AGCCGGGGAGATTAACTGGGATGAGAGCAGGTTTCTAAGCAGCTGTGATTTTCCACAACCGGTGGGC CCATAAATAACACCTATAACCGGTTGCAGCTGGTAGTTTAGAGAGCTGCAGCTGCCGTCGTCCCGGA GGAGGGGGGCCACCTCGTTGAGCATGTCCCTGACGCGCATGTTCTCCCCGACCAGATCCGCCAGAAG GCGCTCGCCGCCCAGGGACAGCAGCTCTTGCAAGGAAGCAAAGTTTTTCAGCGGCTTGAGGCCGTCC GCCGTGGGCATGTTTTTCAGGGTCTGGCTCAGCAGCTCCAGGCGGTCCCAGAGCTCGGTGACGTGCT CTACGGCATCTCTATCCAGCATATCTCCTCGTTTCGCGGGTTGGGGCGACTTTCGCTGTAGGGCACCA AGCGGTGGTCGTCCAGCGGGGCCAGAGTCATGTCCTTCCATGGGCGCAGGGTCCTCGTCAGGGTGGT CTGGGTCACGGTGAAGGGGTGCGCTCCGGGCTGAGCGCTTGCCAAGGTGCGCTTGAGGCTGGTTCTG CTGGTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGCGTCGGCCAGGTAGCATTTGACCATGGTGTCATA GTCCAGCCCCTCCGCGGCGTGTCCCTTGGCGCGCAGCTTGCCCTTGGAGGTGGCGCCGCACGAGGGG CAGAGCAGGCTCTTGAGCGCGTAGAGCTTGGGGGCGAGGAAGACCGATTCGGGGGAGTAGGCGTCC GCGCCGCAGACCCCGCACACGGTCTCGCACTCCACCAGCCAGGTGAGCTCGGGGCGCGCCGGGTCAA AAACCAGGTTTCCCCCATGCTTTTTGATGCGTTTCTTACCTCGGGTCTCCATGAGGTGGTGTCCCCGCT CGGTGACGAAGAGGCTGTCCGTGTCTCCGTAGACCGACTTGAGGGGTCTTTTCTCCAGGGGGGTCCC TCGGTCTTCCTCGTAGAGGAACTCGGACCACTCTGAGACGAAGGCCCGCGTCCAGGCCAGGACGAAG GAGGCTATGTGGGAGGGGTAGCGGTCGTTGTCCACTAGGGGGTCCACCTTCTCCAAGGTGTGAAGAC ACATGTCGCCTTCCTCGGCGTCCAGGAAGGTGATTGGCTTGTAGGTGTAGGCCACGTGACCGGGGGT TCCTGACGGGGGGGTATAAAAGGGGGTGGGGGCGCGCTCGTCGTCACTCTCTTCCGCATCGCTGTCT GCGAGGGCCAGCTGCTGGGGTGAGTATTCCCTCTCGAAGGCGGGCATGACCTCCGCGCTGAGGTTGT CAGTTTCCAAAAACGAGGAGGATTTGATGTTCACCTGTCCCGAGGTGATACCTTTGAGGGTACCCGC GTCCATCTGGTCAGAAAACACGATCTTTTTATTGTCCAGCTTGGTGGCGAACGACCCGTAGAGGGCG TTGGAGAGCAGCTTGGCGATGGAGCGCAGGGTCTGGTTCTTGTCCCTGTCGGCGCGCTCCTTGGCCGC GATGTTGAGCTGCACGTACTCGCGCGCGACGCAGCGCCACTCGGGGAAGACGGTGGTGCGCTCGTCG GGCACCAGGCGCACGCGCCAGCCGCGGTTGTGCAGGGTGACCAGGTCCACGCTGGTGGCGACCTCGC CGCGCAGGCGCTCGTTGGTCCAGCAGAGACGGCCGCCCTTGCGCGAGCAGAAGGGGGGCAGGGGGT CGAGCTGGGTCTCGTCCGGGGGGTCCGCGTCCACGGTGAAAACCCCGGGGCGCAGGCGCGCGTCGA AGTAGTCTATCTTGCAACCTTGCATGTCCAGCGCCTGCTGCCAGTCGCGGGCGGCGAGCGCGCGCTC GTAGGGGTTGAGCGGCGGGCCCCAGGGCATGGGGTGGGTGAGTGCGGAGGCGTACATGCCGCAGAT GTCATAGACGTAGAGGGGCTCCCGCAGGACCCCGATGTAGGTGGGGTAGCAGCGGCCGCCGCGGAT GCTGGCGCGCACGTAGTCATACAGCTCGTGCGAGGGGGCGAGGAGGTCGGGGCCCAGGTTGGTGCG GGCGGGGCGCTCCGCGCGGAAGACGATCTGCCTGAAGATGGCATGCGAGTTGGAAGAGATGGTGGG GCGCTGGAAGACGTTGAAGCTGGCGTCCTGCAGGCCGACGGCGTCGCGCACGAAGGAGGCGTAGGA GTCGCGCAGCTTGTGTACCAGCTCGGCGGTGACCTGCACGTCGAGCGCGCAGTAGTCGAGGGTCTCG CGGATGATGTCATATTTAGCCTGCCCCTTCTTTTTCCACAGCTCGCGGTTGAGGACAAACTCTTCGCG GTCTTTCCAGTACTCTTGGATCGGGAAACCGTCCGGTTCCGAACGGTAAGAGCCTAGCATGTAGAAC TGGTTGACGGCCTGGTAGGCGCAGCAGCCCTTCTCCACGGGGAGGGCGTAGGCCTGCGCGGCCTTGC GGAGCGAGGTGTGGGTCAGGGCGAAGGTGTCCCTGACCATGACTTTGAGGTACTGGTGCTTGAAGTC GGAGTCGTCGCAGCCGCCCCGCTCCCAGAGCGAGAAGTCGGTGCGCTTCTTGGAGCGGGGGTTGGGC AGAGCGAAGGTGACATCGTTGAAGAGGATTTTGCCCGCGCGGGGCATGAAGTTGCGGGTGATGCGG AAGGGCCCCGGCACTTCAGAGCGGTTGTTGATGACCTGGGCGGCGAGCACGATCTCGTCGAAGCCGT TGATGTTGTGGCCCACGATGTAGAGTTCCAGGAAGCGGGGCCGGCCCTTTACGGTGGGCAGCTTCTT TAGCTCTTCGTAGGTGAGCTCCTCGGGCGAGGCGAGGCCGTGCTCGGCCAGGGCCCAGTCCGCGAGG TGCGGGTTGTCTCTGAGGAAGGACTTCCAGAGGTCGCGGGCCAGGAGGGTCTGCAGGCGGTCTCTGA AGGTCCTGAACTGGCGGCCCACGGCCATTTTTTCGGGGGTGATGCAGTAGAAGGTGAGGGGGTCTTG CTGCCAGCGGTCCCAGTCGAGCTGCAGGGCGAGGTCGCGCGCGGCGGTGACCAGGCGCTCGTCGCCC CCGAATTTCATGACCAGCATGAAGGGCACGAGCTGCTTTCCGAAGGCCCCCATCCAAGTGTAGGTCT CTACATCGTAGGTGACAAAGAGGCGCTCCGTGCGAGGATGCGAGCCGATCGGGAAGAACTGGATCT CCCGCCACCAGTTGGAGGAGTGGCTGTTGATGTGGTGGAAGTAGAAGTCCCGTCGCCGGGCCGAACA CTCGTGCTGGCTTTTGTAAAAGCGAGCGCAGTACTGGCAGCGCTGCACGGGCTGTACCTCATGCACG AGATGCACCTTTCGCCCGCGCACGAGGAAGCCGAGGGGAAATCTGAGCCCCCCGCCTGGCTCGCGGC ATGGCTGGTTCTCTTCTACTTTGGATGCGTGTCCGTCTCCGTCTGGCTCCTCGAGGGGTGTTACGGTG GAGCGGACCACCACGCCGCGCGAGCCGCAGGTCCAGATATCGGCGCGCGGCGGTCGGAGTTTGATG ACGACATCGCGCAGCTGGGAGCTGTCCATGGTCTGGAGCTCCCGCGGCGGCGGCAGGTCAGCCGGG AGTTCTTGCAGGTTCACCTCGCAGAGTCGGGCCAGGGCGCGGGGCAGGTCTAGGTGGTACCTGATCT CTAGGGGCGTGTTGGTGGCGGCGTCGATGGCTTGCAGGAGCCCGCAGCCCCGGGGGGCGACGACGG TGCCCCGCGGGGTGGTGGTGGTGGTGGCGGTGCAGCTCAGAAGCGGTGCCGCGGGCGGGCCCCCGG AGGTAGGGGGGGCTCCGGTCCCGCGGGCAGGGGCGGCAGCGGCACGTCGGCGTGGAGCGCGGGCAG GAGTTGGTGCTGTGCCCGGAGGTTGCTGGCGAAGGCGACGACGCGGCGGTTGATCTCCTGGATCTGG CGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCTTGAACCTGAAAGAGAGTTCGACAGAATCAATCT CGGTGTCATTGACCGCGGCCTGGCGCAGGATCTCCTGCACGTCTCCCGAGTTGTCTTGGTAGGCGATC TCGGCCATGAACTGCTCGATCTCTTCCTCCTGGAGGTCTCCGCGTCCGGCGCGTTCCACGGTGGCCGC CAGGTCGTTGGAGATGCGCCCCATGAGCTGCGAGAAGGCGTTGAGTCCGCCCTCGTTCCAGACTCGG CTGTAGACCACGCCCCCCTGGTCATCGCGGGCGCGCATGACCACCTGCGCGAGGTTGAGCTCCACGT GCCGCGCGAAGACGGCGTAGTTGCGCAGACGCTGGAAGAGGTAGTTGAGGGTGGTGGCGGTGTGCT CGGCCACGAAGAAGTTCATGACCCAGCGGCGCAACGTGGATTCGTTGATGTCCCCCAAGGCCTCCAG CCGTTCCATGGCCTCGTAGAAGTCCACGGCGAAGTTGAAAAACTGGGAGTTGCGCGCCGACACGGTC AACTCCTCCTCCAGAAGACGGATGAGCTCGGCGACGGTGTCGCGCACCTCGCGCTCGAAGGCTATGG GGATCTCTTCCTCCGCTAGCATCACCACCTCCTCCTCTTCCTCCTCTTCTGGCACTTCCATGATGGCTT CCTCCTCTTCGGGGGGTGGCGGCGGCGGCGGTGGGGGAGGGGGCGCTCTGCGCCGGCGGCGGCGCA CCGGGAGGCGGTCCACGAAGCGCGCGATCATCTCCCCGCGGCGGCGGCGCATGGTCTCGGTGACGGC GCGGCCGTTCTCCCGGGGGCGCAGTTGGAAGACGCCGCCGGACATCTGGTGCTGGGGCGGGTGGCCG TGAGGCAGCGAGACGGCGCTGACGATGCATCTCAACAATTGCTGCGTAGGTACGCCGCCGAGGGAC CTGAGGGAGTCCATATCCACCGGATCCGAAAACCTTTCGAGGAAGGCGTCTAACCAGTCGCAGTCGC AAGGTAGGCTGAGCACCGTGGCGGGCGGCGGGGGGTGGGGGGAGTGTCTGGCGGAGGTGCTGCTGA TGATGTAATTGAAGTAGGCGGACTTGACACGGCGGATGGTCGACAGGAGCACCATGTCCTTGGGTCC GGCCTGCTGGATGCGGAGGCGGTCGGCTATGCCCCAGGCTTCGTTCTGGCATCGGCGCAGGTCCTTG TAGTAGTCTTGCATGAGCCTTTCCACCGGCACCTCTTCTCCTTCCTCTTCTGCTTCTTCCATGTCTGCTT CGGCCCTGGGGCGGCGCCGCGCCCCCCTGCCCCCCATGCGCGTGACCCCGAACCCCCTGAGCGGTTG GAGCAGGGCCAGGTCGGCGACGACGCGCTCGGCCAGGATGGCCTGCTGCACCTGCGTGAGGGTGGT TTGGAAGTCATCCAAGTCCACGAAGCGGTGGTAGGCGCCCGTGTTGATGGTGTAGGTGCAGTTGGCC ATGACGGACCAGTTGACGGTCTGGTGGCCCGGTTGCGACATCTCGGTGTACCTGAGTCGCGAGTAGG CGCGGGAGTCGAAGACGTAGTCGTTGCAAGTCCGCACCAGGTACTGGTAGCCCACCAGGAAGTGCG GCGGCGGCTGGCGGTAGAGGGGCCAGCGCAGGGTGGCGGGGGCTCCGGGGGCCAGGTCTTCCAGCA TGAGGCGGTGGTAGGCGTAGATGTACCTGGACATCCAGGTGATACCCGCGGCGGTGGTGGAGGCGC GCGGGAAGTCGCGCACCCGGTTCCAGATGTTGCGCAGGGGCAGAAAGTGCTCCATGGTAGGCGTGCT CTGTCCAGTCAGACGCGCGCAGTCGTTGATACTCTAGACCAGGGAAAACGAAAGCCGGTCAGCGGG CACTCTTCCGTGGTCTGGTGAATAGATCGCAAGGGTATCATGGCGGAGGGCCTCGGTTCGAGCCCCG GGTCCGGGCCGGACGGTCCGCCATGATCCACGCGGTTACCGCCCGCGTGTCGAACCCAGGTGTGCGA CGTCAGACAACGGTGGAGTGTTCCTTTTGGCGTTTTTCTGGCCGGGCGCCGGCGCCGCGTAAGAGAC TAAGCCGCGAAAGCGAAAGCAGTAAGTGGCTCGCTCCCCGTAGCCGGAGGGATCCTTGCTAAGGGTT GCGTTGCGGCGAACCCCGGTTCGAATCCCGTACTCGGGCCGGCCGGACCCGCGGCTAAGGTGTTGGA TTGGCCTCCCCCTCGTATAAAGACCCCGCTTGCGGATTGACTCCGGACACGGGGACGAGCCCCTTTTA TTTTTGCTTTCCCCAGATGCATCCGGTGCTGCGGCAGATGCGCCCCCCGCCCCAGCAGCAGCAACAAC ACCAGCAAGAGCGGCAGCAACAGCAGCGGGAGTCATGCAGGGCCCCCTCACCCACCCTCGGCGGGC CGGCCACCTCGGCGTCCGCGGCCGTGTCTGGCGCCTGCGGCGGCGGCGGGGGGCCGGCTGACGACCC CGAGGAGCCCCCGCGGCGCAGGGCCAGACACTACCTGGACCTGGAGGAGGGCGAGGGCCTGGCGCG GCTGGGGGCGCCGTCTCCCGAGCGCCACCCGCGGGTGCAGCTGAAGCGCGACTCGCGCGAGGCGTA CGTGCCTCGGCAGAACCTGTTCAGGGACCGCGCGGGCGAGGAGCCCGAGGAGATGCGGGACAGGAG GTTCAGCGCAGGGCGGGAGCTGCGGCAGGGGCTGAACCGCGAGCGGCTGCTGCGCGAGGAGGACTT TGAGCCCGACGCGCGGACGGGGATCAGCCCCGCGCGCGCGCACGTGGCGGCCGCCGACCTGGTGAC GGCGTACGAGCAGACGGTGAACCAGGAGATCAACTTCCAAAAGAGTTTCAACAACCACGTGCGCAC GCTGGTGGCGCGCGAGGAGGTGACCATCGGGCTGATGCACCTGTGGGACTTTGTAAGCGCGCTGGTG CAGAACCCCAACAGCAAGCCTCTGACGGCGCAGCTGTTCCTGATAGTGCAGCACAGCAGGGACAAC GAGGCGTTTAGGGACGCGCTGCTGAACATCACCGAGCCCGAGGGTCGGTGGCTGCTGGACCTGATTA ACATCCTGCAGAGCATAGTGGTGCAGGAGCGCAGCCTGAGCCTGGCCGACAAGGTGGCGGCCATCA ACTACTCGATGCTGAGCCTGGGCAAGTTTTACGCGCGCAAGATCTACCAGACGCCGTACGTGCCCAT AGACAAGGAGGTGAAGATCGACGGTTTTTACATGCGCATGGCGCTGAAGGTGCTCACCCTGAGCGAC GACCTGGGCGTGTACCGCAACGAGCGCATCCACAAGGCCGTGAGCGTGAGCCGGCGGCGCGAGCTG AGCGACCGCGAGCTGATGCACAGCCTGCAGCGGGCGCTGGCGGGCGCCGGCAGCGGCGACAGGGAG GCGGAGTCCTACTTCGATGCGGGGGCGGACCTGCGCTGGGCGCCCAGCCGGCGGGCCCTGGAGGCC GCGGGGGTCCGCGAGGACTATGACGAGGACGGCGAGGAGGATGAGGAGTACGAGCTAGAGGAGGG CGAGTACCTGGACTAAACCGCGGGTGGTGTTTCCGGTAGATGCAAGACCCGAACGTGGTGGACCCGG CGCTGCGGGCGGCTCTGCAGAGCCAGCCGTCCGGCCTTAACTCCTCAGACGACTGGCGACAGGTCAT GGACCGCATCATGTCGCTGACGGCGCGTAACCCGGACGCGTTCCGGCAGCAGCCGCAGGCCAACAG GCTCTCCGCCATCCTGGAGGCGGTGGTGCCTGCGCGCTCGAACCCCACGCACGAGAAGGTGCTGGCC ATAGTGAACGCGCTGGCCGAGAACAGGGCCATCCGCCCGGACGAGGCCGGGCTGGTGTACGACGCG CTGCTGCAGCGCGTGGCCCGCTACAACAGCGGCAACGTGCAGACCAACCTGGACCGGCTGGTGGGG GACGTGCGCGAGGCGGTGGCGCAGCGCGAGCGCGCGGATCGGCAGGGCAACCTGGGCTCCATGGTG GCGCTGAATGCCTTCCTGAGCACGCAGCCGGCCAACGTGCCGCGGGGGCAGGAAGACTACACCAAC TTTGTGAGCGCGCTGCGGCTGATGGTGACCGAGACCCCCCAGAGCGAGGTGTACCAGTCGGGCCCGG ACTACTTCTTCCAGACCAGCAGACAGGGCCTGCAGACGGTGAACCTGAGCCAGGCTTTCAAGAACCT GCGGGGGCTGTGGGGCGTGAAGGCGCCCACCGGCGACCGGGCGACGGTGTCCAGCCTGCTGACGCC CAACTCGCGCCTGCTGCTGCTGCTGATCGCGCCGTTCACGGACAGCGGCAGCGTGTCCCGGGACACC TACCTGGGGCACCTGCTGACCCTGTACCGCGAGGCCATCGGGCAGGCGCAGGTGGACGAGCACACCT TCCAGGAGATCACCAGCGTGAGCCGCGCGCTGGGGCAGGAGGACACGAGCAGCCTGGAGGCGACTC TGAACTACCTGCTGACCAACCGGCGGCAGAAGATTCCCTCGCTGCACAGCCTGACCTCCGAGGAGGA GCGCATCTTGCGCTACGTGCAGCAGAGCGTGAGCCTGAACCTGATGCGCGACGGGGTGACGCCCAGC GTGGCGCTGGACATGACCGCGCGCAACATGGAACCGGGCATGTACGCCGCGCACCGGCCTTACATCA ACCGCCTGATGGACTACCTGCATCGCGCGGCGGCCGTGAACCCCGAGTACTTTACCAACGCCATCCT GAACCCGCACTGGCTCCCGCCGCCCGGGTTCTACAGCGGGGGCTTCGAGGTCCCGGAGACCAACGAT GGCTTCCTGTGGGACGACATGGACGACAGCGTGTTCTCCCCGCGGCCGCAGGCGCTGGCGGAAGCGT CCCTGCTGCGTCCCAAGAAGGAGGAGGAGGAGGAGGCGAGTCGCCGCCGCGGCAGCAGCGGCGTGG CTTCTCTGTCCGAGCTGGGGGCGGCAGCCGCCGCGCGCCCCGGGTCCCTGGGCGGCAGCCCCTTTCC GAGCCTGGTGGGGTCTCTGCACAGCGAGCGCACCACCCGCCCTCGGCTGCTGGGCGAGGACGAGTAC CTGAATAACTCCCTGCTGCAGCCGGTGCGGGAGAAAAACCTGCCTCCCGCCTTCCCCAACAACGGGA TAGAGAGCCTGGTGGACAAGATGAGCAGATGGAAGACCTATGCGCAGGAGCACAGGGACGCGCCTG CGCTCCGGCCGCCCACGCGGCGCCAGCGCCACGACCGGCAGCGGGGGCTGGTGTGGGATGACGAGG ACTCCGCGGACGATAGCAGCGTGCTGGACCTGGGAGGGAGCGGCAACCCGTTCGCGCACCTGCGCCC CCGCCTGGGGAGGATGTTTTAAAAAAAAAAAAAAAAAGCAAGAAGCATGATGCAAAAATTAAATAA AACTCACCAAGGCCATGGCGACCGAGCGTTGGTTTCTTGTGTTCCCTTCAGTATGCGGCGCGCGGCG ATGTACCAGGAGGGACCTCCTCCCTCTTACGAGAGCGTGGTGGGCGCGGCGGCGGCGGCGCCCTCTT CTCCCTTTGCGTCGCAGCTGCTGGAGCCGCCGTACGTGCCTCCGCGCTACCTGCGGCCTACGGGGGG GAGAAACAGCATCCGTTACTCGGAGCTGGCGCCCCTGTTCGACACCACCCGGGTGTACCTGGTGGAC AACAAGTCGGCGGACGTGGCCTCCCTGAACTACCAGAACGACCACAGCAATTTTTTGACCACGGTCA TCCAGAACAATGACTACAGCCCGAGCGAGGCCAGCACCCAGACCATCAATCTGGATGACCGGTCGC ACTGGGGCGGCGACCTGAAAACCATCCTGCACACCAACATGCCCAACGTGAACGAGTTCATGTTCAC CAATAAGTTCAAGGCGCGGGTGATGGTGTCGCGCTCGCACACCAAGGAAGACCGGGTGGAGCTGAA GTACGAGTGGGTGGAGTTCGAGCTGCCAGAGGGCAACTACTCCGAGACCATGACCATTGACCTGATG AACAACGCGATCGTGGAGCACTATCTGAAAGTGGGCAGGCAGAACGGGGTCCTGGAGAGCGACATC GGGGTCAAGTTCGACACCAGGAACTTCCGCCTGGGGCTGGACCCCGTGACCGGGCTGGTTATGCCCG GGGTGTACACCAACGAGGCCTTCCATCCCGACATCATCCTGCTGCCCGGCTGCGGGGTGGACTTCAC TTACAGCCGCCTGAGCAACCTCCTGGGCATCCGCAAGCGGCAGCCCTTCCAGGAGGGCTTCAGGATC ACCTACGAGGACCTGGAGGGGGGCAACATCCCCGCGCTCCTCGATGTGGAGGCCTACCAGGATAGCT TGAAGGAAAATGAGGCGGGACAGGAGGATACCGCCCCCGCCGCCTCCGCCGCCGCCGAGCAGGGCG AGGATGCTGCTGACACCGCGGCCGCGGACGGGGCAGAGGCCGACCCCGCTATGGTGGTGGAGGCTC CCGAGCAGGAGGAGGACATGAATGACAGTGCGGTGCGCGGAGACACCTTCGTCACCCGGGGGGAGG AAAAGCAAGCGGAGGCCGAGGCCGCGGCCGAGGAAAAGCAACTGGCGGCAGCAGCGGCGGCGGCG GCGTTGGCCGCGGCGGAGGCTGAGTCTGAGGGGACCAAGCCCGCCAAGGAGCCCGTGATTAAGCCC CTGACCGAAGATAGCAAGAAGCGCAGTTACAACCTGCTCAAGGACAGCACCAACACCGCGTACCGC AGCTGGTACCTGGCCTACAACTACGGCGACCCGTCGACGGGGGTGCGCTCCTGGACCCTGCTGTGCA CGCCGGACGTGACCTGCGGCTCGGAGCAGGTGTACTGGTCGCTGCCCGACATGATGCAAGACCCCGT GACCTTCCGCTCCACGCGGCAGGTCAGCAACTTCCCGGTGGTGGGCGCCGAGCTGCTGCCCGTGCAC TCCAAGAGCTTCTACAACGACCAGGCCGTCTACTCCCAGCTCATCCGCCAGTTCACCTCTCTGACCCA CGTGTTCAATCGCTTTCCTGAGAACCAGATTCTGGCGCGCCCGCCCGCCCCCACCATCACCACCGTCA GTGAAAACGTTCCTGCTCTCACAGATCACGGGACGCTACCGCTGCGCAACAGCATCGGAGGAGTCCA GCGAGTGACCGTTACTGACGCCAGACGCCGCACCTGCCCCTACGTTTACAAGGCCTTGGGCATAGTC TCGCCGCGCGTCCTTTCCAGCCGCACTTTTTGAGCAACACCACCATCATGTCCATCCTGATCTCACCC AGCAATAACTCCGGCTGGGGACTGCTGCGCGCGCCCAGCAAGATGTTCGGAGGGGCGAGGAAGCGT TCCGAGCAGCACCCCGTGCGCGTGCGCGGGCACTTCCGCGCCCCCTGGGGAGCGCACAAACGCGGCC GCGCGGGGCGCACCACCGTGGACGACGCCATCGACTCGGTGGTGGAGCAGGCGCGCAACTACAGGC CCGCGGTCTCTACCGTGGACGCGGCCATCCAGACCGTGGTGCGGGGCGCGCGGCGGTACGCCAAGCT GAAGAGCCGCCGGAAGCGCGTGGCCCGCCGCCACCGCCGCCGACCCGGGGCCGCCGCCAAACGCGC CGCCGCGGCCCTGCTTCGCCGGGCCAAGCGCACGGGCCGCCGCGCCGCCATGAGGGCCGCGCGCCGC TTGGCCGCCGGCATCACCGCCGCCACCATGGCCCCCCGTACCCGAAGACGCGCGGCCGCCGCCGCCG CCGCCGCCATCAGTGACATGGCCAGCAGGCGCCGGGGCAACGTGTACTGGGTGCGCGACTCGGTGAC CGGCACGCGCGTGCCCGTGCGCTTCCGCCCCCCGCGGACTTGAGATGATGTGAAAAAACAACACTGA GTCTCCTGCTGTTGTGTGTATCCCAGCGGCGGCGGCGCGCGCAGCGTCATGTCCAAGCGCAAAATCA AAGAAGAGATGCTCCAGGTCGTCGCGCCGGAGATCTATGGGCCCCCGAAGAAGGAAGAGCAGGATT CGAAGCCCCGCAAGATAAAGCGGGTCAAAAAGAAAAAGAAAGATGATGACGATGCCGATGGGGAG GTGGAGTTCCTGCGCGCCACGGCGCCCAGGCGCCCGGTGCAGTGGAAGGGCCGGCGCGTAAAGCGC GTCCTGCGCCCCGGCACCGCGGTGGTCTTCACGCCCGGCGAGCGCTCCACCCGGACTTTCAAGCGCG TCTATGACGAGGTGTACGGCGACGAAGACCTGCTGGAGCAGGCCAACGAGCGCTTCGGAGAGTTTGC TTACGGGAAGCGTCAGCGGGCGCTGGGGAAGGAGGACCTGCTGGCGCTGCCGCTGGACCAGGGCAA CCCCACCCCCAGTCTGAAGCCCGTGACCCTGCAGCAGGTGCTGCCGAGCAGCGCACCCTCCGAGGCG AAGCGGGGTCTGAAGCGCGAGGGCGGCGACCTGGCGCCCACCGTGCAGCTCATGGTGCCCAAGCGG CAGAGGCTGGAGGATGTGCTGGAGAAAATGAAAGTAGACCCCGGTCTGCAGCCGGACATCAGGGTC CGCCCCATCAAGCAGGTGGCGCCGGGCCTCGGCGTGCAGACCGTGGACGTGGTCATCCCCACCGGCA ACTCCCCCGCCGCCGCCACCACTACCGCTGCCTCCACGGACATGGAGACACAGACCGATCCCGCCGC AGCCGCAGCCGCAGCCGCCGCCGCGACCTCCTCGGCGGAGGTGCAGACGGACCCCTGGCTGCCGCCG GCGATGTCAGCTCCCCGCGCGCGTCGCGGGCGCAGGAAGTACGGCGCCGCCAACGCGCTCCTGCCCG AGTACGCCTTGCATCCTTCCATCGCGCCCACCCCCGGCTACCGAGGCTATACCTACCGCCCGCGAAG AGCCAAGGGTTCCACCCGCCGTCCCCGCCGACGCGCCGCCGCCACCACCCGCCGCCGCCGCCGCAGA CGCCAGCCCGCACTGGCTCCAGTCTCCGTGAGGAAAGTGGCGCGCGACGGACACACCCTGGTGCTGC CCAGGGCGCGCTACCACCCCAGCATCGTTTAAAAGCCTGTTGTGGTTCTTGCAGATATGGCCCTCACT TGCCGCCTCCGTTTCCCGGTGCCGGGATACCGAGGAGGAAGATCGCGCCGCAGGAGGGGTCTGGCCG GCCGCGGCCTGAGCGGAGGCAGCCGCCGCGCGCACCGGCGGCGACGCGCCACCAGCCGACGCATGC GCGGCGGGGTGCTGCCCCTGTTAATCCCCCTGATCGCCGCGGCGATCGGCGCCGTGCCCGGGATCGC CTCCGTGGCCTTGCAAGCGTCCCAGAGGCATTGACAGACTTGCAAACTTGCAAATATGGAAAAAAAA ACCCCAATAAAAAAGTCTAGACTCTCACGCTCGCTTGGTCCTGTGACTATTTTGTAGAATGGAAGAC ATCAACTTTGCGTCGCTGGCCCCGCGTCACGGCTCGCGCCCGTTCCTGGGACACTGGAACGATATCG GCACCAGCAACATGAGCGGTGGCGCCTTCAGTTGGGGCTCTCTGTGGAGCGGCATTAAAAGTATCGG GTCTGCCGTTAAAAATTACGGCTCCCGGGCCTGGAACAGCAGCACGGGCCAGATGTTGAGAGACAA GTTGAAAGAGCAGAACTTCCAGCAGAAGGTGGTGGAGGGCCTGGCCTCCGGCATCAACGGGGTGGT GGACCTGGCCAACCAGGCCGTGCAGAATAAGATCAACAGCAGACTGGACCCCCGGCCGCCGGTGGA GGAGGTGCCGCCGGCGCTGGAGACGGTGTCCCCCGATGGGCGTGGCGAGAAGCGCCCGCGGCCCGA TAGGGAAGAGACCACTCTGGTCACGCAGACCGATGAGCCGCCCCCGTATGAGGAGGCCCTGAAGCA AGGTCTGCCCACCACGCGGCCCATCGCGCCCATGGCCACCGGGGTGGTGGGCCGCCACACCCCCGCC ACGCTGGACTTGCCTCCGCCCGCCGATGTGCCGCAGCAGCAGAAGGCGGCACAGCCGGGCCCGCCCG CGACCGCCTCCCGTTCCTCCGCCGGTCCTCTGCGCCGCGCGGCCAGCGGCCCCCGCGGGGGGGTCGC GAGGCACGGCAACTGGCAGAGCACGCTGAACAGCATCGTGGGTCTGGGGGTGCGGTCCGTGAAGCG CCGCCGATGCTACTGAATAGCTTAGCTAACGTGTTGTATGTGTGTATGCGCCCTATGTCGCCGCCAGA GGAGCTGCTGAGTCGCCGCCGTTCGCGCGCCCACCACCACCGCCACTCCGCCCCTCAAGATGGCGAC CCCATCGATGATGCCGCAGTGGTCGTACATGCACATCTCGGGCCAGGACGCCTCGGAGTACCTGAGC CCCGGGCTGGTGCAGTTCGCCCGCGCCACCGAGAGCTACTTCAGCCTGAGTAACAAGTTTAGGAACC CCACGGTGGCGCCCACGCACGATGTGACCACCGACCGGTCTCAGCGCCTGACGCTGCGGTTCATTCC CGTGGACCGCGAGGACACCGCGTACTCGTACAAGGCGCGGTTCACCCTGGCCGTGGGCGACAACCGC GTGCTGGACATGGCCTCCACCTACTTTGACATCCGCGGGGTGCTGGACCGGGGTCCCACTTTCAAGCC CTACTCTGGCACCGCCTACAACTCCCTGGCCCCCAAGGGCGCTCCCAACTCCTGCGAGTGGGAGCAA GAGGAAACTCAGGCAGTTGAAGAAGCAGCAGAAGAGGAAGAAGAAGATGCTGACGGTCAAGCTGA GGAAGAGCAAGCAGCTACCAAAAAGACTCATGTATATGCTCAGGCTCCCCTTTCTGGCGAAAAAATT AGTAAAGATGGTCTGCAAATAGGAACGGACGCTACAGCTACAGAACAAAAACCTATTTATGCAGAC CCTACATTCCAGCCCGAACCCCAAATCGGGGAGTCCCAGTGGAATGAGGCAGATGCTACAGTCGCCG GCGGTAGAGTGCTAAAGAAATCTACTCCCATGAAACCATGCTATGGTTCCTATGCAAGACCCACAAA TGCTAATGGAGGTCAGGGTGTACTAACGGCAAATGCCCAGGGACAGCTAGAATCTCAGGTTGAAATG CAATTCTTTTCAACTTCTGAAAACGCCCGTAACGAGGCTAACAACATTCAGCCCAAATTGGTGCTGTA TAGTGAGGATGTGCACATGGAGACCCCGGATACGCACCTTTCTTACAAGCCCGCAAAAAGCGATGAC AATTCAAAAATCATGCTGGGTCAGCAGTCCATGCCCAACAGACCTAATTACATCGGCTTCAGAGACA ACTTTATCGGCCTCATGTATTACAATAGCACTGGCAACATGGGAGTGCTTGCAGGTCAGGCCTCTCAG TTGAATGCAGTGGTGGACTTGCAAGACAGAAACACAGAACTGTCCTACCAGCTCTTGCTTGATTCCA TGGGTGACAGAACCAGATACTTTTCCATGTGGAATCAGGCAGTGGACAGTTATGACCCAGATGTTAG AATTATTGAAAATCATGGAACTGAAGACGAGCTCCCCAACTATTGTTTCCCTCTGGGTGGCATAGGG GTAACTGACACTTACCAGGCTGTTAAAACCAACAATGGCAATAACGGGGGCCAGGTGACTTGGACA AAAGATGAAACTTTTGCAGATCGCAATGAAATAGGGGTGGGAAACAATTTCGCTATGGAGATCAACC TCAGTGCCAACCTGTGGAGAAACTTCCTGTACTCCAACGTGGCGCTGTACCTACCAGACAAGCTTAA GTACAACCCCTCCAATGTGGACATCTCTGACAACCCCAACACCTACGATTACATGAACAAGCGAGTG GTGGCCCCGGGGCTGGTGGACTGCTACATCAACCTGGGCGCGCGCTGGTCGCTGGACTACATGGACA ACGTCAACCCCTTCAACCACCACCGCAATGCGGGCCTGCGCTACCGCTCCATGCTCCTGGGCAACGG GCGCTACGTGCCCTTCCACATCCAGGTGCCCCAGAAGTTCTTTGCCATCAAGAACCTCCTCCTCCTGC CGGGCTCCTACACCTACGAGTGGAACTTCAGGAAGGATGTCAACATGGTCCTCCAGAGCTCTCTGGG TAACGATCTCAGGGTGGACGGGGCCAGCATCAAGTTCGAGAGCATCTGCCTCTACGCCACCTTCTTC CCCATGGCCCACAACACGGCCTCCACGCTCGAGGCCATGCTCAGGAACGACACCAACGACCAGTCCT TCAATGACTACCTCTCCGCCGCCAACATGCTCTACCCCATACCCGCCAACGCCACCAACGTCCCCATC TCCATCCCCTCGCGCAACTGGGCGGCCTTCCGCGGCTGGGCCTTCACCCGCCTCAAGACCAAGGAGA CCCCCTCCCTGGGCTCGGGATTCGACCCCTACTACACCTACTCGGGCTCCATTCCCTACCTGGACGGC ACCTTCTACCTCAACCACACTTTCAAGAAGGTCTCGGTCACCTTCGACTCCTCGGTCAGCTGGCCGGG CAACGACCGTCTGCTCACCCCCAACGAGTTCGAGATCAAGCGCTCGGTCGACGGGGAGGGCTACAAC GTGGCCCAGTGCAACATGACCAAGGACTGGTTCCTGGTCCAGATGCTGGCCAACTACAACATCGGCT ACCAGGGCTTCTACATCCCAGAGAGCTACAAGGACAGGATGTACTCCTTCTTCAGGAACTTCCAGCC CATGAGCCGGCAGGTGGTGGACCAGACCAAGTACAAGGACTACCAGGAGGTGGGCATCATCCACCA GCACAACAACTCGGGCTTCGTGGGCTACCTCGCCCCCACCATGCGCGAGGGACAGGCCTACCCCGCC AACTTCCCCTATCCGCTCATAGGCAAGACCGCGGTCGACAGCATCACCCAGAAAAAGTTCCTCTGCG ACCGCACCCTCTGGCGCATCCCCTTCTCCAGCAACTTCATGTCCATGGGTGCGCTCTCGGACCTGGGC CAGAACTTGCTCTACGCCAACTCCGCCCACGCCCTCGACATGACCTTCGAGGTCGACCCCATGGACG AGCCCACCCTTCTCTATGTTCTGTTCGAAGTCTTTGACGTGGTCCGGGTCCACCAGCCGCACCGCGGC GTCATCGAGACCGTGTACCTGCGTACGCCCTTCTCGGCCGGCAACGCCACCACCTAAAGAAGCAAGC CGCAGTCATCGCCGCCTGCATGCCGTCGGGTTCCACCGAGCAAGAGCTCAGGGCCATCGTCAGAGAC CTGGGATGCGGGCCCTATTTTTTGGGCACCTTCGACAAGCGCTTCCCTGGCTTTGTCTCCCCACACAA GCTGGCCTGCGCCATCGTCAACACGGCCGGCCGCGAGACCGGGGGCGTGCACTGGCTGGCCTTCGCC TGGAACCCGCGCTCCAAAACATGCTTCCTCTTTGACCCCTTCGGCTTTTCGGACCAGCGGCTCAAGCA AATCTACGAGTTCGAGTACGAGGGCTTGCTGCGTCGCAGCGCCATCGCCTCCTCGCCCGACCGCTGC GTCACCCTCGAAAAGTCCACCCAGACCGTGCAGGGGCCCGACTCGGCCGCCTGCGGTCTCTTCTGCT GCATGTTTCTGCACGCCTTTGTGCACTGGCCTCAGAGTCCCATGGACCGCAACCCCACCATGAACTTG CTGACGGGGGTGCCCAACTCCATGCTCCAGAGCCCCCAGGTCGAGCCCACCCTGCGCCGCAACCAGG AGCAGCTCTACAGCTTCCTGGAGCGCCACTCGCCTTACTTCCGCCGCCACAGCGCACAGATCAGGAG GGCCACCTCCTTCTGCCACTTGCAAGAGATGCAAGAAGGGTAATAACGATGTACACACTTTTTTTCTC AATAAATGGCATCTTTTTATTTATACAAGCTCTCTGGGGTATTCATTTCCCACCACCACCCGCCGTTGT CGCCATCTGGCTCTATTTAGAAATCGAAAGGGTTCTGCCGGGAGTCGCCGTGCGCCACGGGCAGGGA CACGTTGCGATACTGGTAGCGGGTGCCCCACTTGAACTCGGGCACCACCAGGCGAGGCAGCTCGGGG AAGTTTTCGCTCCACAGGCTGCGGGTCAGCACCAGCGCGTTCATCAGGTCGGGCGCCGAGATCTTGA AGTCGCAGTTGGGGCCGCCGCCCTGCGCGCGCGAGTTGCGGTACACCGGGTTGCAGCACTGGAACAC CAACAGCGCCGGGTGCTTCACGCTGGCCAGCACGCTGCGGTCGGAGATCAGCTCGGCGTCCAGGTCC TCCGCGTTGCTCAGCGCGAACGGGGTCATCTTGGGCACTTGCCGCCCCAGGAAGGGCGCGTGCCCCG GTTTCGAGTTGCAGTCGCAGCGCAGCGGGATCAGCAGGTGCCCGTGCCCGGACTCGGCGTTGGGGTA CAGCGCGCGCATGAAGGCCTGCATCTGGCGGAAGGCCATCTGGGCCTTGGCGCCCTCCGAGAAGAAC ATGCCGCAGGACTTGCCCGAGAACTGGTTTGCGGGGCAGCTGGCGTCGTGCAGGCAGCAGCGCGCGT CGGTGTTGGCGATCTGCACCACGTTGCGCCCCCACCGGTTCTTCACGATCTTGGCCTTGGACGATTGC TCCTTCAGCGCGCGCTGCCCGTTCTCGCTGGTCACATCCATCTCGATCACATGTTCCTTGTTCACCATG CTGCTGCCGTGCAGACACTTCAGCTCGCCCTCCGTCTCGGTGCAGCGGTGCTGCCACAGCGCGCAGC CCGTGGGCTCGAAAGACTTGTAGGTCACCTCCGCGAAGGACTGCAGGTACCCCTGCAAAAAGCGGCC CATCATGGTCACGAAGGTCTTGTTGCTGCTGAAGGTCAGCTGCAGCCCGCGGTGCTCCTCGTTCAGCC AGGTCTTGCACACGGCCGCCAGCGCCTCCACCTGGTCGGGCAGCATCTTGAAGTTCACCTTCAGCTCA TTCTCCACGTGGTACTTGTCCATCAGCGTGCGCGCCGCCTCCATGCCCTTCTCCCAGGCCGACACCAG CGGCAGGCTCACGGGGTTCTTCACCATCACCGTGGCCGCCGCCTCCGCCGCGCTTTCGCTTTCCGCCC CGCTGTTCTCTTCCTCTTCCTCCTCTTCCTCGCCGCCGCCCACTCGCAGCCCCCGCACCACGGGGTCGT CTTCCTGCAGGCGCTGCACCTTGCGCTTGCCGTTGCGCCCCTGCTTGATGCGCACGGGCGGGTTGCTG AAGCCCACCATCACCAGCGCGGCCTCTTCTTGCTCGTCCTCGCTGTCCAGAATGACCTCCGGGGAGG GGGGGTTGGTCATCCTCAGTACCGAGGCACGCTTCTTTTTCTTCCTGGGGGCGTTCGCCAGCTCCGCG GCTGCGGCCGCTGCCGAGGTCGAAGGCCGAGGGCTGGGCGTGCGCGGCACCAGCGCGTCCTGCGAG CCGTCCTCGTCCTCCTCGGACTCGAGACGGAGGCGGGCCCGCTTCTTCGGGGGCGCGCGGGGCGGCG GAGGCGGCGGCGGCGACGGAGACGGGGACGAGACATCGTCCAGGGTGGGTGGACGGCGGGCCGCG CCGCGTCCGCGCTCGGGGGTGGTCTCGCGCTGGTCCTCTTCCCGACTGGCCATCTCCCACTGCTCCTT CTCCTATAGGCAGAAAGAGATCATGGAGTCTCTCATGCGAGTCGAGAAGGAGGAGGACAGCCTAAC CGCCCCCTCTGAGCCCTCCACCACCGCCGCCACCACCGCCAATGCCGCCGCGGACGACGCGCCCACC GAGACCACCGCCAGTACCACCCTCCCCAGCGACGCACCCCCGCTCGAGAATGAAGTGCTGATCGAGC AGGACCCGGGTTTTGTGAGCGGAGAGGAGGATGAGGTGGATGAGAAGGAGAAGGAGGAGGTCGCC GCCTCAGTGCCAAAAGAGGATAAAAAGCAAGACCAGGACGACGCAGATAAGGATGAGACAGCAGT CGGGCGGGGGAACGGAAGCCATGATGCTGATGACGGCTACCTAGACGTGGGAGACGACGTGCTGCT TAAGCACCTGCACCGCCAGTGCGTCATCGTCTGCGACGCGCTGCAGGAGCGCTGCGAAGTGCCCCTG GACGTGGCGGAGGTCAGCCGCGCCTACGAGCGGCACCTCTTCGCGCCGCACGTGCCCCCCAAGCGCC GGGAGAACGGCACCTGCGAGCCCAACCCGCGTCTCAACTTCTACCCGGTCTTCGCGGTACCCGAGGT GCTGGCCACCTACCACATCTTTTTCCAAAACTGCAAGATCCCCCTCTCCTGCCGCGCCAACCGCACCC GCGCCGACAAAACCCTGACCCTGCGGCAGGGCGCCCACATACCTGATATCGCCTCTCTGGAGGAAGT GCCCAAGATCTTCGAGGGTCTCGGTCGCGACGAGAAACGGGCGGCGAACGCTCTGCACGGAGACAG CGAAAACGAGAGTCACTCGGGGGTGCTGGTGGAGCTCGAGGGCGACAACGCGCGCCTGGCCGTACT CAAGCGCAGCATAGAGGTCACCCACTTTGCCTACCCGGCGCTCAACCTGCCCCCCAAGGTCATGAGT GTGGTCATGGGCGAGCTCATCATGCGCCGCGCCCAGCCCCTGGCCGCGGATGCAAACTTGCAAGAGT CCTCCGAGGAAGGCCTGCCCGCGGTCAGCGACGAGCAGCTGGCGCGCTGGCTGGAGACCCGCGACC CCGCGCAGCTGGAGGAGCGGCGCAAGCTCATGATGGCCGCGGTGCTGGTCACCGTGGAGCTCGAGT GTCTGCAGCGCTTCTTCGCGGACCCCGAGATGCAGCGCAAGCTCGAGGAGACCCTGCACTACACCTT CCGCCAGGGCTACGTGCGCCAGGCCTGCAAGATCTCCAACGTGGAGCTCTGCAACCTGGTCTCCTAC CTGGGCATCCTGCACGAGAACCGCCTCGGGCAGAACGTCCTGCACTCCACCCTCAAAGGGGAGGCGC GCCGCGACTACATCCGCGACTGCGCCTACCTCTTCCTCTGCTACACCTGGCAGACGGCCATGGGGGTC TGGCAGCAGTGCCTGGAGGAGCGCAACCTCAAGGAGCTGGAAAAGCTCCTCAAGCGCACCCTCAGG GACCTCTGGACGGGCTTCAACGAGCGCTCGGTGGCCGCCGCGCTGGCGGACATCATCTTTCCCGAGC GCCTGCTCAAGACCCTGCAGCAGGGCCTGCCCGACTTCACCAGCCAGAGCATGCTGCAGAACTTCAG GACTTTCATCCTGGAGCGCTCGGGCATCCTGCCGGCCACTTGCTGCGCGCTGCCCAGCGACTTCGTGC CCATCAAGTACAGGGAGTGCCCGCCGCCGCTCTGGGGCCACTGCTACCTCTTCCAGCTGGCCAACTA CCTCGCCTACCACTCGGACCTCATGGAAGACGTGAGCGGCGAGGGCCTGCTCGAGTGCCACTGCCGC TGCAACCTCTGCACGCCCCACCGCTCTCTAGTCTGCAACCCGCAGCTGCTCAGCGAGAGTCAGATTAT CGGTACCTTCGAGCTGCAGGGTCCCTCGCCTGACGAGAAGTCCGCGGCTCCAGGGCTGAAACTCACT CCGGGGCTGTGGACTTCCGCCTACCTACGCAAATTTGTACCTGAGGACTACCACGCCCACGAGATCA GGTTCTACGAAGACCAATCCCGCCCGCCCAAGGCGGAGCTCACCGCCTGCGTCATCACCCAGGGGCA CATCCTGGGCCAATTGCAAGCCATCAACAAAGCCCGCCGAGAGTTCTTGCTGAAAAAGGGTCGGGGG GTGTACCTGGACCCCCAGTCCGGCGAGGAGCTAAACCCGCTACCCCCGCCGCCGCCCCAGCAGCGGG ACCTTGCTTCCCAGGATGGCACCCAGAAAGAAGCAGCAGCCGCCGCCGCCGCCGCAGCCATACATGC TTCTGGAGGAAGAGGAGGAGGACTGGGACAGTCAGGCAGAGGAGGTTTCGGACGAGGAGCAGGAG GAGATGATGGAAGACTGGGAGGAGGACAGCAGCCTAGACGAGGAAGCTTCAGAGGCCGAAGAGGT GGCAGACGCAACACCATCGCCCTCGGTCGCAGCCCCCTCGCCGGGGCCCCTGAAATCCTCCGAACCC AGCACCAGCGCTATAACCTCCGCTCCTCCGGCGCCGGCGCCACCCGCCCGCAGACCCAACCGTAGAT GGGACACCACAGGAACCGGGGTCGGTAAGTCCAAGTGCCCGCCGCCGCCACCGCAGCAGCAGCAGC AGCAGCGCCAGGGCTACCGCTCGTGGCGCGGGCACAAGAACGCCATAGTCGCCTGCTTGCAAGACTG CGGGGGCAACATCTCTTTCGCCCGCCGCTTCCTGCTATTCCACCACGGGGTCGCCTTTCCCCGCAATG TCCTGCATTACTACCGTCATCTCTACAGCCCCTACTGCAGCGGCGACCCAGAGGCGGCAGCGGCAGC CACAGCGGCGACCACCACCTAGGAAGATATCCTCCGCGGGCAAGACAGCGGCAGCAGCGGCCAGGA GACCCGCGGCAGCAGCGGCGGGAGCGGTGGGCGCACTGCGCCTCTCGCCCAACGAACCCCTCTCGAC CCGGGAGCTCAGACACAGGATCTTCCCCACTTTGTATGCCATCTTCCAACAGAGCAGAGGCCAGGAG CAGGAGCTGAAAATAAAAAACAGATCTCTGCGCTCCCTCACCCGCAGCTGTCTGTATCACAAAAGCG AAGATCAGCTTCGGCGCACGCTGGAGGACGCGGAGGCACTCTTCAGCAAATACTGCGCGCTCACTCT TAAAGACTAGCTCCGCGCCCTTCTCGAATTTAGGCGGGAGAAAACTACGTCATCGCCGGCCGCCGCC CAGCCCGCCCAGCCGAGATGAGCAAAGAGATTCCCACGCCATACATGTGGAGCTACCAGCCGCAGA TGGGACTCGCGGCGGGAGCGGCCCAGGACTACTCCACCCGCATGAACTACATGAGCGCGGGACCCC ACATGATCTCACAGGTCAACGGGATCCGCGCCCAGCGAAACCAAATACTGCTGGAACAGGCGGCCA TCACCGCCACGCCCCGCCATAATCTCAACCCCCGAAATTGGCCCGCCGCCCTCGTGTACCAGGAAAC CCCCTCCGCCACCACCGTACTACTTCCGCGTGACGCCCAGGCCGAAGTCCAGATGACTAACTCAGGG GCGCAGCTCGCGGGCGGCTTTCGTCACGGGGCGCGGCCGCTCCGACCAGGTATAAGACACCTGATGA TCAGAGGCCGAGGTATCCAGCTCAACGACGAGTCGGTGAGCTCTTCGCTCGGTCTCCGTCCGGACGG AACTTTCCAGCTCGCCGGATCCGGCCGCTCTTCGTTCACGCCCCGCCAGGCGTACCTGACTCTGCAGA CCTCGTCCTCGGAGCCCCGCTCCGGCGGCATCGGAACCCTCCAGTTCGTGGAGGAGTTCGTGCCCTCG GTCTACTTCAACCCCTTCTCGGGACCTCCCGGACGCTACCCCGACCAGTTCATTCCGAACTTTGACGC GGTGAAGGACTCGGCGGACGGCTACGACTGAATGTCAGGTGTCGAGGCAGAGCAGCTTCGCCTGAG ACACCTCGAGCACTGCCGCCGCCACAAGTGCTTCGCCCGCGGTTCTGGTGAGTTCTGCTACTTTCAGC TACCCGAGGAGCATACCGAGGGGCCGGCGCACGGCGTCCGCCTGACCACCCAGGGCGAGGTTACCT GTTCCCTCATCCGGGAGTTTACCCTCCGTCCCCTGCTAGTGGAGCGGGAGCGGGGTCCCTGTGTCCTA ACTATCGCCTGCAACTGCCCTAACCCTGGATTACATCAAGATCTTTGCTGTCATCTCTGTGCTGAGTTT AATAAACGCTGAGATCAGAATCTACTGGGGCTCCTGTCGCCATCCTGTGAACGCCACCGTCTTCACCC ACCCCGACCAGGCCCAGGCGAACCTCACCTGCGGTCTGCATCGGAGGGCCAAGAAGTACCTCACCTG GTACTTCAACGGCACCCCCTTTGTGGTTTACAACAGCTTCGACGGGGACGGAGTCTCCCTGAAAGAC CAGCTCTCCGGTCTCAGCTACTCCATCCACAAGAACACCACCCTCCAACTCTTCCCTCCCTACCTGCC GGGAACCTACGAGTGCGTCACCGGCCGCTGCACCCACCTCACCCGCCTGATCGTAAACCAGAGCTTT CCGGGAACAGATAACTCCCTCTTCCCCAGAACAGGAGGTGAGCTCAGGAAACTCCCCGGGGACCAG GGCGGAGACGTACCTTCGACCCTTGTGGGGTTAGGATTTTTTATTACCGGGTTGCTGGCTCTTTTAAT CAAAGTTTCCTTGAGATTTGTTCTTTCCTTCTACGTGTATGAACACCTCAACCTCCAATAACTCTACCC TTTCTTCGGAATCAGGTGACTTCTCTGAAATCGGGCTTGGTGTGCTGCTTACTCTGTTGATTTTTTTCC TTATCATACTCAGCCTTCTGTGCCTCAGGCTCGCCGCCTGCTGCGCACACATCTATATCTACTGCTGGT TGCTCAAGTGCAGGGGTCGCCACCCAAGATGAACAGGTACATGGTCCTATCGATCCTAGGCCTGCTG GCCCTGGCGGCCTGCAGCGCCGCCAAAAAAGAGATTACCTTTGAGGAGCCCGCTTGCAATGTAACTT TCAAGCCCGAGGGTGACCAATGCACCACCCTCGTCAAATGCGTTACCAATCATGAGAGGCTGCGCAT CGACTACAAAAACAAAACTGGCCAGTTTGCGGTCTATAGTGTGTTTACGCCCGGAGACCCCTCTAAC TACTCTGTCACCGTCTTCCAGGGCGGACAGTCTAAGATATTCAATTACACTTTCCCTTTTTATGAGTTA TGCGATGCGGTCATGTACATGTCAAAACAGTACAACCTGTGGCCTCCCTCTCCCCAGGCGTGTGTGG AAAATACTGGGTCTTACTGCTGTATGGCTTTCGCAATCACTACGCTCGCTCTAATCTGCACGGTGCTA TACATAAAATTCAGGCAGAGGCGAATCTTTATCGATGAAAAGAAAATGCCTTGATCGCTAACACCGG CTTTCTATCTGCAGAATGAATGCAATCACCTCCCTACTAATCACCACCACCCTCCTTGCGATTGCCCA TGGGTTGACACGAATCGAAGTGCCAGTGGGGTCCAATGTCACCATGGTGGGCCCCGCCGGCAATTCC ACCCTCATGTGGGAAAAATTTGTCCGCAATCAATGGGTTCATTTCTGCTCTAACCGAATCAGTATCAA GCCCAGAGCCATCTGCGATGGGCAAAATCTAACTCTGATCAATGTGCAAATGATGGATGCTGGGTAC TATTACGGGCAGCGGGGAGAAATCATTAATTACTGGCGACCCCACAAGGACTACATGCTGCATGTAG TCGAGGCACTTCCCACTACCACCCCCACTACCACCTCTCCCACCACCACCACCACTACTACTACTACT ACTACTACTACTACTACTACCACTACCGCTGCCCGCCATACCCGCAAAAGCACCATGATTAGCACAA AGCCCCCTCGTGCTCACTCCCACGCCGGCGGGCCCATCGGTGCGACCTCAGAAACCACCGAGCTTTG CTTCTGCCAATGCACTAACGCCAGCGCTCATGAACTGTTCGACCTGGAGAATGAGGATGTCCAGCAG AGCTCCGCTTGCCTGACCCAGGAGGCTGTGGAGCCCGTTGCCCTGAAGCAGATCGGTGATTCAATAA TTGACTCTTCTTCTTTTGCCACTCCCGAATACCCTCCCGATTCTACTTTCCACATCACGGGTACCAAAG ACCCTAACCTCTCTTTCTACCTGATGCTGCTGCTCTGTATCTCTGTGGTCTCTTCCGCGCTGATGTTAC TGGGGATGTTCTGCTGCCTGATCTGCCGCAGAAAGAGAAAAGCTCGCTCTCAGGGCCAACCACTGAT GCCCTTCCCCTACCCCCCGGATTTTGCAGATAACAAGATATGAGCTCGCTGCTGACACTAACCGCTTT ACTAGCCTGCGCTCTAACCCTTGTCGCTTGCGACTCGAGATTCCACAATGTCACAGCTGTGGCAGGAG AAAATGTTACTTTCAACTCCACGGCCGATACCCAGTGGTCGTGGAGTGGCTCAGGTAGCTACTTAACT ATCTGCAATAGCTCCACTTCCCCCGGCATATCCCCAACCAAGTACCAATGCAATGCCAGCCTGTTCAC CCTCATCAACGCTTCCACCCTGGACAATGGACTCTATGTAGGCTATGTACCCTTTGGTGGGCAAGGAA AGACCCACGCTTACAACCTGGAAGTTCGCCAGCCCAGAACCACTACCCAAGCTTCTCCCACCACCAC CACCACCACCACCATCACCAGCAGCAGCAGCAGCAGCAGCCACAGCAGCAGCAGCAGATTATTGAC TTTGGTTTTGGCCAGCTCATCTGCCGCTACCCAGGCCATCTACAGCTCTGTGCCCGAAACCACTCAGA TCCACCGCCCAGAAACGACCACCGCCACCACCCTACACACCTCCAGCGATCAGATGCCGACCAACAT CACCCCCTTGGCTCTTCAAATGGGACTTACAAGCCCCACTCCAAAACCAGTGGATGCGGCCGAGGTC TCCGCCCTCGTCAATGACTGGGCGGGGCTGGGAATGTGGTGGTTCGCCATAGGCATGATGGCGCTCT GCCTGCTTCTGCTCTGGCTCATCTGCTGCCTCCACCGCAGGCGAGCCAGACCCCCCATCTATAGACCC ATCATTGTCCTGAACCCCGATAATGATGGGATCCATAGATTGGATGGCCTGAAAAACCTACTTTTTTC TTTTACAGTATGATAAATTGAGACATGCCTCGCATTTTCTTGTACATGTTCCTTCTCCCACCTTTTCTG GGGTGTTCTACGCTGGCCGCTGTGTCTCACCTGGAGGTAGACTGCCTCTCACCCTTCACTGTCTACCT GCTTTACGGATTGGTCACCCTCACTCTCATCTGCAGCCTAATCACAGTAATCATCGCCTTCATCCAGT GCATTGATTACATCTGTGTGCGCCTCGCATACTTCAGACACCACCCGCAGTACCGAGACAGGAACAT TGCCCAACTTCTAAGACTGCTCTAATCATGCATAAGACTGTGATCTGCCTTCTGATCCTCTGCATCCT GCCCACCCTCACCTCCTGCCAGTACACCACAAAATCTCCGCGCAAAAGACATGCCTCCTGCCGCTTCA CCCAACTGTGGAATATACCCAAATGCTACAACGAAAAGAGCGAGCTCTCCGAAGCTTGGCTGTATGG GGTCATCTGTGTCTTAGTTTTCTGCAGCACTGTCTTTGCCCTCATAATCTACCCCTACTTTGATTTGGG ATGGAACGCGATCGATGCCATGAATTACCCCACCTTTCCCGCACCCGAGATAATTCCACTGCGACAA GTTGTACCCGTTGTCGTTAATCAACGCCCCCCATCCCCTACGCCCACTGAAATCAGCTACTTTAACCT AACAGGCGGAGATGACTGACGCCCTAGATCTAGAAATGGACGGCATCAGTACCGAGCAGCGTCTCCT AGAGAGGCGCAGGCAGGCGGCTGAGCAAGAGCGCCTCAATCAGGAGCTCCGAGATCTCGTTAACCT GCACCAGTGCAAAAGAGGCATCTTTTGTCTGGTAAAGCAGGCCAAAGTCACCTACGAGAAGACCGG CAACAGCCACCGCCTCAGTTACAAATTGCCCACCCAGCGCCAGAAGCTGGTGCTCATGGTGGGTGAG AATCCCATCACCGTCACCCAGCACTCGGTAGAGACCGAGGGGTGTCTGCACTCCCCCTGTCGGGGTC CAGAAGACCTCTGCACCCTGGTAAAGACCCTGTGCGGTCTCAGAGATTTAGTCCCCTTTAACTAATCA AACACTGGAATCAATAAAAAGAATCACTTACTTAAAATCAGACAGCAGGTCTCTGTCCAGTTTATTC AGCAGCACCTCCTTCCCCTCCTCCCAACTCTGGTACTCCAAACGCCTTCTGGCGGCAAACTTCCTCCA CACCCTGAAGGGAATGTCAGATTCTTGCTCCTGTCCCTCCGCACCCACTATCTTCATGTTGTTGCAGA TGAAGCGCACCAAAACGTCTGACGAGAGCTTCAACCCCGTGTACCCCTATGACACGGAAAGCGGCCC TCCCTCCGTCCCTTTCCTCACCCCTCCCTTCGTGTCTCCCGATGGATTCCAAGAAAGTCCCCCCGGGGT CCTGTCTCTGAACCTGGCCGAGCCCCTGGTCACTTCCCACGGCATGCTCGCCCTGAAAATGGGAAGT GGCCTCTCCCTGGACGACGCTGGCAACCTCACCTCTCAAGATATCACCACCGCTAGCCCTCCCCTCAA AAAAACCAAGACCAACCTCAGCCTAGAAACCTCATCCCCCCTAACTGTGAGCACCTCAGGCGCCCTC ACCGTAGCAGCCGCCGCTCCCCTGGCGGTGGCCGGCACCTCCCTCACCATGCAATCAGAGGCCCCCC TGACAGTACAGGATGCAAAACTCACCCTGGCCACCAAAGGCCCCCTGACCGTGTCTGAAGGCAAACT GGCCTTGCAAACATCGGCCCCGCTGACGGCCGCTGACAGCAGCACCCTCACAGTCAGTGCCACACCA CCCCTTAGCACAAGCAATGGCAGCTTGGGTATTGACATGCAAGCCCCCATTTACACCACCAATGGAA AACTAGGACTTAACTTTGGCGCTCCCCTGCATGTGGTAGACAGCCTAAATGCACTGACTGTAGTTACT GGCCAAGGTCTTACGATAAACGGAACAGCCCTACAAACTAGAGTCTCAGGTGCCCTCAACTATGACA CATCAGGAAACCTAGAATTGAGAGCTGCAGGGGGTATGCGAGTTGATGCAAATGGTCAACTTATCCT TGATGTAGCTTACCCATTTGATGCACAAAACAATCTCAGCCTTAGGCTTGGACAGGGACCCCTGTTTG TTAACTCTGCCCACAACTTGGATGTTAACTACAACAGAGGCCTCTACCTGTTCACATCTGGAAATACC AAAAAGCTAGAAGTTAATATCAAAACAGCCAAGGGTCTCATTTATGATGACACTGCTATAGCAATCA ATGCGGGTGATGGGCTACAGTTTGACTCAGGCTCAGATACAAATCCATTAAAAACTAAACTTGGATT AGGACTGGATTATGACTCCAGCAGAGCCATAATTGCTAAACTGGGAACTGGCCTAAGCTTTGACAAC ACAGGTGCCATCACAGTAGGCAACAAAAATGATGACAAGCTTACCTTGTGGACCACACCAGACCCAT CCCCTAACTGTAGAATCTATTCAGAGAAAGATGCTAAATTCACACTTGTTTTGACTAAATGCGGCAGT CAGGTGTTGGCCAGCGTTTCTGTTTTATCTGTAAAAGGTAGCCTTGCGCCCATCAGTGGCACAGTAAC TAGTGCTCAGATTGTCCTCAGATTTGATGAAAATGGAGTTCTACTAAGCAATTCTTCCCTTGACCCTC AATACTGGAACTACAGAAAAGGTGACCTTACAGAGGGCACTGCATATACCAACGCAGTGGGATTTAT GCCCAACCTCACAGCATACCCAAAAACACAGAGCCAAACTGCTAAAAGCAACATTGTAAGTCAGGTT TACTTGAATGGGGACAAATCCAAACCCATGACCCTCACCATTACCCTCAATGGAACTAATGAAACAG GAGATGCCACAGTAAGCACTTACTCCATGTCATTCTCATGGAACTGGAATGGAAGTAATTACATTAA TGAAACGTTCCAAACCAACTCCTTCACCTTCTCCTACATCGCCCAAGAATAAAAAGCATGACGCTGTT GATTTGATTCAATGTGTTTCTGTTTTATTTTCAAGCACAACAAAATCATTCAAGTCATTCTTCCATCTT AGCTTAATAGACACAGTAGCTTAATAGACCCAGTAGTGCAAAGCCCCATTCTAGCTTATAGATCAGA CAGTGATAATTAACCACCACCACCACCATACCTTTTGATTCAGGAAATCATGATCATCACAGGATCCT AGTCTTCAGGCCGCCCCCTCCCTCCCAAGACACAGAATACACAGTCCTCTCCCCCCGACTGGCTTTAA ATAACACCATCTGGTTGGTCACAGACATGTTCTTAGGGGTTATATTCCACACGGTCTCCTGCCGCGCC AGGCGCTCGTCGGTGATGTTGATAAACTCTCCCGGCAGCTCGCTCAAGTTCACGTCGCTGTCCAGCGG CTGAACCTCCGGCTGACGCGATAACTGTGCGACCGGCTGCTGGACGAACGGAGGCCGCGCCTACAAG GGGGTAGAGTCATAATCCTCGGTCAGGATAGGGCGGTGATGCAGCAGCAGCGAGCGAAACATCTGC TGCCGCCGCCGCTCCGTCCGGCAGGAAAACAACACGCCGGTGGTCTCCTCCGCGATAATCCGCACCG CCCGCAGCATCAGCTTCCTCGTTCTCCGCGCGCAGCACCTCACCCTTATCTCGCTCAAATCGGCGCAG TAGGTACAGCACAGCACCACGATGTTATTCATGATCCCACAGTGCAGGGCGCTGTATCCAAAGCTCA TGCCGGGAACCACCGCCCCCACGTGGCCATCGTACCACAAGCGCACGTAAATCAAGTGTCGACCCCT CATGAACGCGCTGGACACAAACATTACTTCCTTGGGCATGTTGTAATTCACCACCTCCCGGTACCAGA TAAACCTCTGGTTGAACAGGGCACCTTCCACCACCATCCTGAACCAAGAGGCCAGAACCTGCCCACC GGCTATGCACTGCAGGGAACCCGGGTTGGAACAATGACAATGCAGACTCCAAGGCTCGTAACCGTG GATCATCCGGCTGCTGAAGGCATCGATGTTGGCACAACACAGACACACGTGCATGCACTTTCTCATG ATTAGCAGCTCTTCCCTCGTCAGGATCATATCCCAAGGAATAACCCATTCTTGAATCAACGTAAAACC CACACAGCAGGGAAGGCCTCGCACATAACTCACGTTGTGCATGGTCAGCGTGTTGCATTCCGGAAAC AGCGGATGATCCTCCAGTATCGAGGCGCGGGTCTCCTTCTCACAGGGAGGTAAAGGGTCCCTGCTGT ACGGACTGCGCCGGGACGACCGAGATCGTGTTGAGCGTAGTGTCATGGAAAAGGGAACGCCGGACG TGGTCATACTTCTTGAAGCAGAACCAGGTTCGCGCGTGGCAGGCCTCCTTGCGTCTGCGGTCTCGCCG TCTAGCTCGCTCCGTGTGATAGTTGTAGTACAGCCACTCCCGCAGAGCGTCGAGGCGCACCCTGGCTT CCGGATCTATGTAGACTCCGTCTTGCACCGCGGCCCTGATAATATCCACCACCGTAGAATAAGCAAC ACCCAGCCAAGCAATACACTCGCTCTGCGAGCGGCAGACAGGAGGAGCGGGCAGAGATGGGAGAAC CATGATAAAAAACTTTTTTTAAAGAATATTTTCCAATTCTTCGAAAGTAAGATCTATCAAGTGGCAGC GCTCCCCTCCACTGGCGCGGTCAAACTCTACGGCCAAAGCACAGACAACGGCATTTCTAAGATGTTC CTTAATGGCGTCCAAAAGACACACCGCTCTCAAGTTGCAGTAAACTATGAATGAAAACCCATCCGGC TGATTTTCCAATATAGACGCGCCGGCAGCGTCCACCAAACCCAGATAATTTTCTTCTCTCCAGCGGTT TACGATCTGTCTAAGCAAATCCCTTATATCAAGTCCGACCATGCCAAAAATCTGCTCAAGAGCGCCCT CCACCTTCATGTACAAGCAGCGCATCATGATTGCAAAAATTCAGGTTCTTCAGAGACCTGTATAAGA TTCAAAATGGGAACATTAACAAAAATTCCTCTGTCGCGCAGATCCCTTCGCAGGGCAAGCTGAACAT AATCAGACAGGTCCGAACGGACCAGTGAGGCCAAATCCCCACCAGGAACCAGATCCAGAGACCCTA TACTGATTATGACGCGCATACTCGGGGCTATGCTGACCAGCGTAGCGCCGATGTAGGCGTGCTGCAT GGGCGGCGAGATAAAATGCAAAGTGCTGGTTAAAAAATCAGGCAAAGCCTCGCGCAAAAAAGCTAA CACATCATAATCATGCTCATGCAGGTAGTTGCAGGTAAGCTCAGGAACCAAAACGGAATAACACACG ATTTTCCTCTCAAACATGACTTCGCGGATACTGCGTAAAACAAAAAATTATAAATAAAAAATTAATT AAATAACTTAAACATTGGAAGCCTGTCTCACAACAGGAAAAACCACTTTAATCAACATAAGACGGGC CACGGGCATGCCGGCATAGCCGTAAAAAAATTGGTCCCCGTGATTAACAAGTACCACAGACAGCTCC CCGGTCATGTCGGGGGTCATCATGTGAGACTCTGTATACACGTCTGGATTGTGAACATCAGACAAAC AAAGAAATCGAGCCACGTAGCCCGGAGGTATAATCACCCGCAGGCGGAGGTACAGCAAAACGACCC CCATAGGAGGAATCACAAAATTAGTAGGAGAAAAAAATACATAAACACCAGAAAAACCCTGTTGCT GAGGCAAAATAGCGCCCTCCCGATCCAAAACAACATAAAGCGCTTCCACAGGAGCAGCCATAACAA AGACCCGAGTCTTACCAGTAAAAGAAAAAAGATCTCTCAACGCAGCACCAGCACCAACACTTCGCA GTGTAAAAGGCCAAGTGCCGAGAGAGTATATATAGGAATAAAAAGTGACGTAAACGGGCAAAGTCC AAAAAACGCCCAGAAAAACCGCACGCGAACCTACGCCCCGAAACGAAAGCCAAAAAACACTAGAC ACTCCCTTCCGGCGTCAACTTCCGCTTTCCCACGCTACGTCACTTGCCCCAGTCAAACAAACTACATA TCCCGAACTTCCAAGTCGCCACGCCCAAAACACCGCCTACACCTCCCCGCCCGCCGGCCCGCCCCCA AACCCGCCTCCCGCCCCGCGCCCCGCCCCGCGCCGCCCATCTCATTATCATATTGGCTTCAATCCAAA ATAAGGTATATTATTGATGATGGTTTAAACGGATCCTCTAGAGTCGACCTGCAGGCATGCAAGCTTG AGTATTCTATAGTGTCACCTAAATAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTG TTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAA TGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTG CCAGCTGCATTAATGAATCGGCCAACGCGAACCCCTTGCGGCCGCCCGGGCCGTCGACCAATTCTCA TGTTTGACAGCTTATCATCGAATTTCTGCCATTCATCCGCTTATTATCACTTATTCAGGCGTAGCAACC AGGCGTTTAAGGGCACCAATAACTGCCTTAAAAAAATTACGCCCCGCCCTGCCACTCATCGCAGTAC TGTTGTAATTCATTAAGCATTCTGCCGACATGGAAGCCATCACAAACGGCATGATGAACCTGAATCG CCAGCGGCATCAGCACCTTGTCGCCTTGCGTATAATATTTGCCCATGGTGAAAACGGGGGCGAAGAA GTTGTCCATATTGGCCACGTTTAAATCAAAACTGGTGAAACTCACCCAGGGATTGGCTGAGACGAAA AACATATTCTCAATAAACCCTTTAGGGAAATAGGCCAGGTTTTCACCGTAACACGCCACATCTTGCG AATATATGTGTAGAAACTGCCGGAAATCGTCGTGGTATTCACTCCAGAGCGATGAAAACGTTTCAGT TTGCTCATGGAAAACGGTGTAACAAGGGTGAACACTATCCCATATCACCAGCTCACCGTCTTTCATTG CCATACGGAATTCCGGATGAGCATTCATCAGGCGGGCAAGAATGTGAATAAAGGCCGGATAAAACT TGTGCTTATTTTTCTTTACGGTCTTTAAAAAGGCCGTAATATCCAGCTGAACGGTCTGGTTATAGGTA CATTGAGCAACTGACTGAAATGCCTCAAAATGTTCTTTACGATGCCATTGGGATATATCAACGGTGGT ATATCCAGTGATTTTTTTCTCCATTTTAGCTTCCTTAGCTCCTGAAAATCTCGATAACTCAAAAAATAC GCCCGGTAGTGATCTTATTTCATTATGGTGAAAGTTGGAACCTCTTACGTGCCGATCAACGTCTCATT TTCGCCAAAAGTTGGCCCAGGGCTTCCCGGTATCAACAGGGACACCAGGATTTATTTATTCTGCGAA GTGATCTTCCGTCACAGGTATTTATTCGCGATAAGCTCATGGAGCGGCGTAACCGTCGCACAGGAAG GACAGAGAAAGCGCGGATCTGGGAAGTGACGGACAGAACGGTCAGGACCTGGATTGGGGAGGCGGT TGCCGCCGCTGCTGCTGACGGTGTGACGTTCTCTGTTCCGGTCACACCACATACGTTCCGCCATTCCT ATGCGATGCACATGCTGTATGCCGGTATACCGCTGAAAGTTCTGCAAAGCCTGATGGGACATAAGTC CATCAGTTCAACGGAAGTCTACACGAAGGTTTTTGCGCTGGATGTGGCTGCCCGGCACCGGGTGCAG TTTGCGATGCCGGAGTCTGATGCGGTTGCGATGCTGAAACAATTATCCTGAGAATAAATGCCTTGGC CTTTATATGGAAATGTGGAACTGAGTGGATATGCTGTTTTTGTCTGTTAAACAGAGAAGCTGGCTGTT ATCCACTGAGAAGCGAACGAAACAGTCGGGAAAATCTCCCATTATCGTAGAGATCCGCATTATTAAT CTCAGGAGCCTGTGTAGCGTTTATAGGAAGTAGTGTTCTGTCATGATGCCTGCAAGCGGTAACGAAA ACGATTTGAATATGCCTTCAGGAACAATAGAAATCTTCGTGCGGTGTTACGTTGAAGTGGAGCGGAT TATGTCAGCAATGGACAGAACAACCTAATGAACACAGAACCATGATGTGGTCTGTCCTTTTACAGCC AGTAGTGCTCGCCGCAGTCGAGCGACAGGGCGAAGCCCTCGAGTGAGCGAGGAAGCACCAGGGAAC AGCACTTATATATTCTGCTTACACACGATGCCTGAAAAAACTTCCCTTGGGGTTATCCACTTATCCAC GGGGATATTTTTATAATTATTTTTTTTATAGTTTTTAGATCTTCTTTTTTAGAGCGCCTTGTAGGCCTTT ATCCATGCTGGTTCTAGAGAAGGTGTTGTGACAAATTGCCCTTTCAGTGTGACAAATCACCCTCAAAT GACAGTCCTGTCTGTGACAAATTGCCCTTAACCCTGTGACAAATTGCCCTCAGAAGAAGCTGTTTTTT CACAAAGTTATCCCTGCTTATTGACTCTTTTTTATTTAGTGTGACAATCTAAAAACTTGTCACACTTCA CATGGATCTGTCATGGCGGAAACAGCGGTTATCAATCACAAGAAACGTAAAAATAGCCCGCGAATC GTCCAGTCAAACGACCTCACTGAGGCGGCATATAGTCTCTCCCGGGATCAAAAACGTATGCTGTATC TGTTCGTTGACCAGATCAGAAAATCTGATGGCACCCTACAGGAACATGACGGTATCTGCGAGATCCA TGTTGCTAAATATGCTGAAATATTCGGATTGACCTCTGCGGAAGCCAGTAAGGATATACGGCAGGCA TTGAAGAGTTTCGCGGGGAAGGAAGTGGTTTTTTATCGCCCTGAAGAGGATGCCGGCGATGAAAAAG GCTATGAATCTTTTCCTTGGTTTATCAAACGTGCGCACAGTCCATCCAGAGGGCTTTACAGTGTACAT ATCAACCCATATCTCATTCCCTTCTTTATCGGGTTACAGAACCGGTTTACGCAGTTTCGGCTTAGTGA AACAAAAGAAATCACCAATCCGTATGCCATGCGTTTATACGAATCCCTGTGTCAGTATCGTAAGCCG GATGGCTCAGGCATCGTCTCTCTGAAAATCGACTGGATCATAGAGCGTTACCAGCTGCCTCAAAGTT ACCAGCGTATGCCTGACTTCCGCCGCCGCTTCCTGCAGGTCTGTGTTAATGAGATCAACAGCAGAACT CCAATGCGCCTCTCATACATTGAGAAAAAGAAAGGCCGCCAGACGACTCATATCGTATTTTCCTTCC GCGATATCACTTCCATGACGACAGGATAGTCTGAGGGTTATCTGTCACAGATTTGAGGGTGGTTCGTC ACATTTGTTCTGACCTACTGAGGGTAATTTGTCACAGTTTTGCTGTTTCCTTCAGCCTGCATGGATTTT CTCATACTTTTTGAACTGTAATTTTTAAGGAAGCCAAATTTGAGGGCAGTTTGTCACAGTTGATTTCC TTCTCTTTCCCTTCGTCATGTGACCTGATATCGGGGGTTAGTTCGTCATCATTGATGAGGGTTGATTAT CACAGTTTATTACTCTGAATTGGCTATCCGCGTGTGTACCTCTACCTGGAGTTTTTCCCACGGTGGAT ATTTCTTCTTGCGCTGAGCGTAAGAGCTATCTGACAGAACAGTTCTTCTTTGCTTCCTCGCCAGTTCGC TCGCTATGCTCGGTTACACGGCTGCGGCGAGCGCTAGTGATAATAAGTGACTGAGGTATGTGCTCTTC TTATCTCCTTTTGTAGTGTTGCTCTTATTTTAAACAACTTTGCGGTTTTTTGATGACTTTGCGATTTTGT TGTTGCTTTGCAGTAAATTGCAAGATTTAATAAAAAAACGCAAAGCAATGATTAAAGGATGTTCAGA ATGAAACTCATGGAAACACTTAACCAGTGCATAAACGCTGGTCATGAAATGACGAAGGCTATCGCCA TTGCACAGTTTAATGATGACAGCCCGGAAGCGAGGAAAATAACCCGGCGCTGGAGAATAGGTGAAG CAGCGGATTTAGTTGGGGTTTCTTCTCAGGCTATCAGAGATGCCGAGAAAGCAGGGCGACTACCGCA CCCGGATATGGAAATTCGAGGACGGGTTGAGCAACGTGTTGGTTATACAATTGAACAAATTAATCAT ATGCGTGATGTGTTTGGTACGCGATTGCGACGTGCTGAAGACGTATTTCCACCGGTGATCGGGGTTGC TGCCCATAAAGGTGGCGTTTACAAAACCTCAGTTTCTGTTCATCTTGCTCAGGATCTGGCTCTGAAGG GGCTACGTGTTTTGCTCGTGGAAGGTAACGACCCCCAGGGAACAGCCTCAATGTATCACGGATGGGT ACCAGATCTTCATATTCATGCAGAAGACACTCTCCTGCCTTTCTATCTTGGGGAAAAGGACGATGTCA CTTATGCAATAAAGCCCACTTGCTGGCCGGGGCTTGACATTATTCCTTCCTGTCTGGCTCTGCACCGT ATTGAAACTGAGTTAATGGGCAAATTTGATGAAGGTAAACTGCCCACCGATCCACACCTGATGCTCC GACTGGCCATTGAAACTGTTGCTCATGACTATGATGTCATAGTTATTGACAGCGCGCCTAACCTGGGT ATCGGCACGATTAATGTCGTATGTGCTGCTGATGTGCTGATTGTTCCCACGCCTGCTGAGTTGTTTGA CTACACCTCCGCACTGCAGTTTTTCGATATGCTTCGTGATCTGCTCAAGAACGTTGATCTTAAAGGGT TCGAGCCTGATGTACGTATTTTGCTTACCAAATACAGCAATAGTAATGGCTCTCAGTCCCCGTGGATG GAGGAGCAAATTCGGGATGCCTGGGGAAGCATGGTTCTAAAAAATGTTGTACGTGAAACGGATGAA GTTGGTAAAGGTCAGATCCGGATGAGAACTGTTTTTGAACAGGCCATTGATCAACGCTCTTCAACTG GTGCCTGGAGAAATGCTCTTTCTATTTGGGAACCTGTCTGCAATGAAATTTTCGATCGTCTGATTAAA CCACGCTGGGAGATTAGATAATGAAGCGTGCGCCTGTTATTCCAAAACATACGCTCAATACTCAACC GGTTGAAGATACTTCGTTATCGACACCAGCTGCCCCGATGGTGGATTCGTTAATTGCGCGCGTAGGA GTAATGGCTCGCGGTAATGCCATTACTTTGCCTGTATGTGGTCGGGATGTGAAGTTTACTCTTGAAGT GCTCCGGGGTGATAGTGTTGAGAAGACCTCTCGGGTATGGTCAGGTAATGAACGTGACCAGGAGCTG CTTACTGAGGACGCACTGGATGATCTCATCCCTTCTTTTCTACTGACTGGTCAACAGACACCGGCGTT CGGTCGAAGAGTATCTGGTGTCATAGAAATTGCCGATGGGAGTCGCCGTCGTAAAGCTGCTGCACTT ACCGAAAGTGATTATCGTGTTCTGGTTGGCGAGCTGGATGATGAGCAGATGGCTGCATTATCCAGAT TGGGTAACGATTATCGCCCAACAAGTGCTTATGAACGTGGTCAGCGTTATGCAAGCCGATTGCAGAA TGAATTTGCTGGAAATATTTCTGCGCTGGCTGATGCGGAAAATATTTCACGTAAGATTATTACCCGCT GTATCAACACCGCCAAATTGCCTAAATCAGTTGTTGCTCTTTTTTCTCACCCCGGTGAACTATCTGCCC GGTCAGGTGATGCACTTCAAAAAGCCTTTACAGATAAAGAGGAATTACTTAAGCAGCAGGCATCTAA CCTTCATGAGCAGAAAAAAGCTGGGGTGATATTTGAAGCTGAAGAAGTTATCACTCTTTTAACTTCTG TGCTTAAAACGTCATCTGCATCAAGAACTAGTTTAAGCTCACGACATCAGTTTGCTCCTGGAGCGACA GTATTGTATAAGGGCGATAAAATGGTGCTTAACCTGGACAGGTCTCGTGTTCCAACTGAGTGTATAG AGAAAATTGAGGCCATTCTTAAGGAACTTGAAAAGCCAGCACCCTGATGCGACCACGTTTTAGTCTA CGTTTATCTGTCTTTACTTAATGTCCTTTGTTACAGGCCAGAAAGCATAACTGGCCTGAATATTCTCTC TGGGCCCACTGTTCCACTTGTATCGTCGGTCTGATAATCAGACTGGGACCACGGTCCCACTCGTATCG TCGGTCTGATTATTAGTCTGGGACCACGGTCCCACTCGTATCGTCGGTCTGATTATTAGTCTGGGACC ACGGTCCCACTCGTATCGTCGGTCTGATAATCAGACTGGGACCACGGTCCCACTCGTATCGTCGGTCT GATTATTAGTCTGGGACCATGGTCCCACTCGTATCGTCGGTCTGATTATTAGTCTGGGACCACGGTCC CACTCGTATCGTCGGTCTGATTATTAGTCTGGAACCACGGTCCCACTCGTATCGTCGGTCTGATTATT AGTCTGGGACCACGGTCCCACTCGTATCGTCGGTCTGATTATTAGTCTGGGACCACGATCCCACTCGT GTTGTCGGTCTGATTATCGGTCTGGGACCACGGTCCCACTTGTATTGTCGATCAGACTATCAGCGTGA GACTACGATTCCATCAATGCCTGTCAAGGGCAAGTATTGACATGTCGTCGTAACCTGTAGAACGGAG TAACCTCGGTGTGCGGTTGTATGCCTGCTGTGGATTGCTGCTGTGTCCTGCTTATCCACAACATTTTGC GCACGGTTATGTGGACAAAATACCTGGTTACCCAGGCCGTGCCGGCACGTTAACCGGGCTGCATCCG ATGCAAGTGTGTCGCTGTCGACGAGCTCGCGAGCTCGGACATGAGGTTGCCCCGTATTCAGTGTCGC TGATTTGTATTGTCTGAAGTTGTTTTTACGTTAAGTTGATGCAGATCAATTAATACGATACCTGCGTC ATAATTGATTATTTGACGTGGTTTGATGGCCTCCACGCACGTTGTGATATGTAGATGATAATCATTAT CACTTTACGGGTCCTTTCCGGTGATCCGACAGGTTACGGGGCGGCGACCTCGCGGGTTTTCGCTATTT ATGAAAATTTTCCGGTTTAAGGCGTTTCCGTTCTTCTTCGTCATAACTTAATGTTTTTATTTAAAATAC CCTCTGAAAAGAAAGGAAACGACAGGTGCTGAAAGCGAGCTTTTTGGCCTCTGTCGTTTCCTTTCTCT GTTTTTGTCCGTGGAATGAACAATGGAAGTCCGAGCTCATCGCTAATAACTTCGTATAGCATACATTA TACGAAGTTATATTCGATGCGGCCGCAAGGGGTTCGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTG GCTTAACTATGCGGCATCAGAGCAGATTGTACTGAGAGTGCACCATATGCGGTGTGAAATACCGCAC AGATGCGTAAGGAGAAAATACCGCATCAGGCGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAG GGCGATCGGTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATT AAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAATTGTAATAC GACTCACTATAGGGCGAATTCGAGCTCGGTACCCGGGGATCCTCGTTTAAAC Polynucleotide sequence encoding wild type ChAd155 SEQ ID NO: 10 CATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAATGAGATGGGCGGCGCGGGGCG GGAGGCGGGTCCGGGGGCGGGCCGGCGGGCGGGGCGGTGTGGCGGAAGTGGACTTTGTAAGTGTGG CGGATGTGACTTGCTAGTGCCGGGCGCGGTAAAAGTGACGTTTTCCGTGCGCGACAACGCCCACGGG AAGTGACATTTTTCCCGCGGTTTTTACCGGATGTTGTAGTGAATTTGGGCGTAACCAAGTAAGATTTG GCCATTTTCGCGGGAAAACTGAAACGGGGAAGTGAAATCTGATTAATTTCGCGTTAGTCATACCGCG TAATATTTGTCGAGGGCCGAGGGACTTTGGCCGATTACGTGGAGGACTCGCCCAGGTGTTTTTTGAG GTGAATTTCCGCGTTCCGGGTCAAAGTCTCCGTTTTATTATTATAGTCAGCTGACGCGGAGTGTATTT ATACCCTCTGATCTCGTCAAGTGGCCACTCTTGAGTGCCAGCGAGTAGAGTTTTCTCCTCTGCCGCTC TCCGCTCCGCTCCGCTCGGCTCTGACACCGGGGAAAAAATGAGACATTTCACCTACGATGGCGGTGT GCTCACCGGCCAGCTGGCTGCTGAAGTCCTGGACACCCTGATCGAGGAGGTATTGGCCGATAATTAT CCTCCCTCGACTCCTTTTGAGCCACCTACACTTCACGAACTCTACGATCTGGATGTGGTGGGGCCCAG CGATCCGAACGAGCAGGCGGTTTCCAGTTTTTTTCCAGAGTCCATGTTGTTGGCCAGCCAGGAGGGG GTCGAACTTGAGACCCCTCCTCCGATCGTGGATTCCCCCGATCCGCCGCAGCTGACTAGGCAGCCCG AGCGCTGTGCGGGACCTGAGACTATGCCCCAGCTGCTACCTGAGGTGATCGATCTCACCTGTAATGA GTCTGGTTTTCCACCCAGCGAGGATGAGGACGAAGAGGGTGAGCAGTTTGTGTTAGATTCTGTGGAA CAACCCGGGCGAGGATGCAGGTCTTGTCAATATCACCGGAAAAACACAGGAGACTCCCAGATTATGT GTTCTCTGTGTTATATGAAGATGACCTGTATGTTTATTTACAGTAAGTTTATCATCTGTGGGCAGGTG GGCTATAGTGTGGGTGGTGGTCTTTGGGGGGTTTTTTAATATATGTCAGGGGTTATGCTGAAGACTTT TTTATTGTGATTTTTAAAGGTCCAGTGTCTGAGCCCGAGCAAGAACCTGAACCGGAGCCTGAGCCTTC TCGCCCCAGGAGAAAGCCTGTAATCTTAACTAGACCCAGCGCACCGGTAGCGAGAGGCCTCAGCAGC GCGGAGACCACCGACTCCGGTGCTTCCTCATCACCCCCGGAGATTCACCCCCTGGTGCCCCTGTGTCC CGTTAAGCCCGTTGCCGTGAGAGTCAGTGGGCGGCGGTCTGCTGTGGAGTGCATTGAGGACTTGCTT TTTGATTCACAGGAACCTTTGGACTTGAGCTTGAAACGCCCCAGGCATTAAACCTGGTCACCTGGACT GAATGAGTTGACGCCTATGTTTGCTTTTGAATGACTTAATGTGTATAGATAATAAAGAGTGAGATAAT GTTTTAATTGCATGGTGTGTTTAACTTGGGCGGAGTCTGCTGGGTATATAAGCTTCCCTGGGCTAAAC TTGGTTACACTTGACCTCATGGAGGCCTGGGAGTGTTTGGAGAACTTTGCCGGAGTTCGTGCCTTGCT GGACGAGAGCTCTAACAATACCTCTTGGTGGTGGAGGTATTTGTGGGGCTCTCCCCAGGGCAAGTTA GTTTGTAGAATCAAGGAGGATTACAAGTGGGAATTTGAAGAGCTTTTGAAATCCTGTGGTGAGCTAT TGGATTCTTTGAATCTAGGCCACCAGGCTCTCTTCCAGGAGAAGGTCATCAGGACTTTGGATTTTTCC ACACCGGGGCGCATTGCAGCCGCGGTTGCTTTTCTAGCTTTTTTGAAGGATAGATGGAGCGAAGAGA CCCACTTGAGTTCGGGCTACGTCCTGGATTTTCTGGCCATGCAACTGTGGAGAGCATGGATCAGACA CAAGAACAGGCTGCAACTGTTGTCTTCCGTCCGCCCGTTGCTGATTCCGGCGGAGGAGCAACAGGCC GGGTCAGAGGACCGGGCCCGTCGGGATCCGGAGGAGAGGGCACCGAGGCCGGGCGAGAGGAGCGC GCTGAACCTGGGAACCGGGCTGAGCGGCCATCCACATCGGGAGTGAATGTCGGGCAGGTGGTGGAT CTTTTTCCAGAACTGCGGCGGATTTTGACTATTAGGGAGGATGGGCAATTTGTTAAGGGTCTTAAGAG GGAGAGGGGGGCTTCTGAGCATAACGAGGAGGCCAGTAATTTAGCTTTTAGCTTGATGACCAGACAC CGTCCAGAGTGCATCACTTTTCAGCAGATTAAGGACAATTGTGCCAATGAGTTGGATCTGTTGGGTCA GAAGTATAGCATAGAGCAGCTGACCACTTACTGGCTGCAGCCGGGTGATGATCTGGAGGAAGCTATT AGGGTGTATGCTAAGGTGGCCCTGCGGCCCGATTGCAAGTACAAGCTCAAGGGGCTGGTGAATATCA GGAATTGTTGCTACATTTCTGGCAACGGGGCGGAGGTGGAGATAGAGACCGAAGACAGGGTGGCTTT CAGATGCAGCATGATGAATATGTGGCCGGGGGTGCTGGGCATGGACGGGGTGGTGATTATGAATGTG AGGTTCACGGGGCCCAACTTTAACGGCACGGTGTTTTTGGGGAACACCAACCTGGTCCTGCACGGGG TGAGCTTCTATGGGTTTAACAACACCTGTGTGGAGGCCTGGACCGATGTGAAGGTCCGCGGTTGCGC CTTTTATGGATGTTGGAAGGCCATAGTGAGCCGCCCTAAGAGCAGGAGTTCCATTAAGAAATGCTTG TTTGAGAGGTGCACCTTGGGGATCCTGGCCGAGGGCAACTGCAGGGTGCGCCACAATGTGGCCTCCG AGTGCGGTTGCTTCATGCTAGTCAAGAGCGTGGCGGTAATCAAGCATAATATGGTGTGCGGCAACAG CGAGGACAAGGCCTCACAGATGCTGACCTGCACGGATGGCAACTGCCACTTGCTGAAGACCATCCAT GTAACCAGCCACAGCCGGAAGGCCTGGCCCGTGTTCGAGCACAACTTGCTGACCCGCTGCTCCTTGC ATCTGGGCAACAGGCGGGGGGTGTTCCTGCCCTATCAATGCAACTTTAGTCACACCAAGATCTTGCT AGAGCCCGAGAGCATGTCCAAGGTGAACTTGAACGGGGTGTTTGACATGACCATGAAGATCTGGAA GGTGCTGAGGTACGACGAGACCAGGTCCCGGTGCAGACCCTGCGAGTGCGGGGGCAAGCATATGAG GAACCAGCCCGTGATGCTGGATGTGACCGAGGAGCTGAGGACAGACCACTTGGTTCTGGCCTGCACC AGGGCCGAGTTTGGTTCTAGCGATGAAGACACAGATTGAGGTGGGTGAGTGGGCGTGGCCTGGGGT GGTCATGAAAATATATAAGTTGGGGGTCTTAGGGTCTCTTTATTTGTGTTGCAGAGACCGCCGGAGCC ATGAGCGGGAGCAGCAGCAGCAGCAGTAGCAGCAGCGCCTTGGATGGCAGCATCGTGAGCCCTTAT TTGACGACGCGGATGCCCCACTGGGCCGGGGTGCGTCAGAATGTGATGGGCTCCAGCATCGACGGCC GACCCGTCCTGCCCGCAAATTCCGCCACGCTGACCTATGCGACCGTCGCGGGGACGCCGTTGGACGC CACCGCCGCCGCCGCCGCCACCGCAGCCGCCTCGGCCGTGCGCAGCCTGGCCACGGACTTTGCATTC CTGGGACCACTGGCGACAGGGGCTACTTCTCGGGCCGCTGCTGCCGCCGTTCGCGATGACAAGCTGA CCGCCCTGCTGGCGCAGTTGGATGCGCTTACTCGGGAACTGGGTGACCTTTCTCAGCAGGTCATGGCC CTGCGCCAGCAGGTCTCCTCCCTGCAAGCTGGCGGGAATGCTTCTCCCACAAATGCCGTTTAAGATA AATAAAACCAGACTCTGTTTGGATTAAAGAAAAGTAGCAAGTGCATTGCTCTCTTTATTTCATAATTT TCCGCGCGCGATAGGCCCTAGACCAGCGTTCTCGGTCGTTGAGGGTGCGGTGTATCTTCTCCAGGAC GTGGTAGAGGTGGCTCTGGACGTTGAGATACATGGGCATGAGCCCGTCCCGGGGGTGGAGGTAGCA CCACTGCAGAGCTTCATGCTCCGGGGTGGTGTTGTAGATGATCCAGTCGTAGCAGGAGCGCTGGGCA TGGTGCCTAAAAATGTCCTTCAGCAGCAGGCCGATGGCCAGGGGGAGGCCCTTGGTGTAAGTGTTTA CAAAACGGTTAAGTTGGGAAGGGTGCATTCGGGGAGAGATGATGTGCATCTTGGACTGTATTTTTAG ATTGGCGATGTTTCCGCCCAGATCCCTTCTGGGATTCATGTTGTGCAGGACCACCAGTACAGTGTATC CGGTGCACTTGGGGAATTTGTCATGCAGCTTAGAGGGAAAAGCGTGGAAGAACTTGGAGACGCCTTT GTGGCCTCCCAGATTTTCCATGCATTCGTCCATGATGATGGCAATGGGCCCGCGGGAGGCAGCTTGG GCAAAGATATTTCTGGGGTCGCTGACGTCGTAGTTGTGTTCCAGGGTGAGGTCGTCATAGGCCATTTT TACAAAGCGCGGGCGGAGGGTGCCCGACTGGGGGATGATGGTCCCCTCTGGCCCTGGGGCGTAGTTG CCCTCGCAGATCTGCATTTCCCAGGCCTTAATCTCGGAGGGGGGAATCATATCCACCTGCGGGGCGA TGAAGAAAACGGTTTCCGGAGCCGGGGAGATTAACTGGGATGAGAGCAGGTTTCTAAGCAGCTGTG ATTTTCCACAACCGGTGGGCCCATAAATAACACCTATAACCGGTTGCAGCTGGTAGTTTAGAGAGCT GCAGCTGCCGTCGTCCCGGAGGAGGGGGGCCACCTCGTTGAGCATGTCCCTGACGCGCATGTTCTCC CCGACCAGATCCGCCAGAAGGCGCTCGCCGCCCAGGGACAGCAGCTCTTGCAAGGAAGCAAAGTTTT TCAGCGGCTTGAGGCCGTCCGCCGTGGGCATGTTTTTCAGGGTCTGGCTCAGCAGCTCCAGGCGGTCC CAGAGCTCGGTGACGTGCTCTACGGCATCTCTATCCAGCATATCTCCTCGTTTCGCGGGTTGGGGCGA CTTTCGCTGTAGGGCACCAAGCGGTGGTCGTCCAGCGGGGCCAGAGTCATGTCCTTCCATGGGCGCA GGGTCCTCGTCAGGGTGGTCTGGGTCACGGTGAAGGGGTGCGCTCCGGGCTGAGCGCTTGCCAAGGT GCGCTTGAGGCTGGTTCTGCTGGTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGCGTCGGCCAGGTAGC ATTTGACCATGGTGTCATAGTCCAGCCCCTCCGCGGCGTGTCCCTTGGCGCGCAGCTTGCCCTTGGAG GTGGCGCCGCACGAGGGGCAGAGCAGGCTCTTGAGCGCGTAGAGCTTGGGGGCGAGGAAGACCGAT TCGGGGGAGTAGGCGTCCGCGCCGCAGACCCCGCACACGGTCTCGCACTCCACCAGCCAGGTGAGCT CGGGGCGCGCCGGGTCAAAAACCAGGTTTCCCCCATGCTTTTTGATGCGTTTCTTACCTCGGGTCTCC ATGAGGTGGTGTCCCCGCTCGGTGACGAAGAGGCTGTCCGTGTCTCCGTAGACCGACTTGAGGGGTC TTTTCTCCAGGGGGGTCCCTCGGTCTTCCTCGTAGAGGAACTCGGACCACTCTGAGACGAAGGCCCG CGTCCAGGCCAGGACGAAGGAGGCTATGTGGGAGGGGTAGCGGTCGTTGTCCACTAGGGGGTCCAC CTTCTCCAAGGTGTGAAGACACATGTCGCCTTCCTCGGCGTCCAGGAAGGTGATTGGCTTGTAGGTGT AGGCCACGTGACCGGGGGTTCCTGACGGGGGGGTATAAAAGGGGGTGGGGGCGCGCTCGTCGTCAC TCTCTTCCGCATCGCTGTCTGCGAGGGCCAGCTGCTGGGGTGAGTATTCCCTCTCGAAGGCGGGCATG ACCTCCGCGCTGAGGTTGTCAGTTTCCAAAAACGAGGAGGATTTGATGTTCACCTGTCCCGAGGTGA TACCTTTGAGGGTACCCGCGTCCATCTGGTCAGAAAACACGATCTTTTTATTGTCCAGCTTGGTGGCG AACGACCCGTAGAGGGCGTTGGAGAGCAGCTTGGCGATGGAGCGCAGGGTCTGGTTCTTGTCCCTGT CGGCGCGCTCCTTGGCCGCGATGTTGAGCTGCACGTACTCGCGCGCGACGCAGCGCCACTCGGGGAA GACGGTGGTGCGCTCGTCGGGCACCAGGCGCACGCGCCAGCCGCGGTTGTGCAGGGTGACCAGGTCC ACGCTGGTGGCGACCTCGCCGCGCAGGCGCTCGTTGGTCCAGCAGAGACGGCCGCCCTTGCGCGAGC AGAAGGGGGGCAGGGGGTCGAGCTGGGTCTCGTCCGGGGGGTCCGCGTCCACGGTGAAAACCCCGG GGCGCAGGCGCGCGTCGAAGTAGTCTATCTTGCAACCTTGCATGTCCAGCGCCTGCTGCCAGTCGCG GGCGGCGAGCGCGCGCTCGTAGGGGTTGAGCGGCGGGCCCCAGGGCATGGGGTGGGTGAGTGCGGA GGCGTACATGCCGCAGATGTCATAGACGTAGAGGGGCTCCCGCAGGACCCCGATGTAGGTGGGGTA GCAGCGGCCGCCGCGGATGCTGGCGCGCACGTAGTCATACAGCTCGTGCGAGGGGGCGAGGAGGTC GGGGCCCAGGTTGGTGCGGGCGGGGCGCTCCGCGCGGAAGACGATCTGCCTGAAGATGGCATGCGA GTTGGAAGAGATGGTGGGGCGCTGGAAGACGTTGAAGCTGGCGTCCTGCAGGCCGACGGCGTCGCG CACGAAGGAGGCGTAGGAGTCGCGCAGCTTGTGTACCAGCTCGGCGGTGACCTGCACGTCGAGCGC GCAGTAGTCGAGGGTCTCGCGGATGATGTCATATTTAGCCTGCCCCTTCTTTTTCCACAGCTCGCGGT TGAGGACAAACTCTTCGCGGTCTTTCCAGTACTCTTGGATCGGGAAACCGTCCGGTTCCGAACGGTA AGAGCCTAGCATGTAGAACTGGTTGACGGCCTGGTAGGCGCAGCAGCCCTTCTCCACGGGGAGGGCG TAGGCCTGCGCGGCCTTGCGGAGCGAGGTGTGGGTCAGGGCGAAGGTGTCCCTGACCATGACTTTGA GGTACTGGTGCTTGAAGTCGGAGTCGTCGCAGCCGCCCCGCTCCCAGAGCGAGAAGTCGGTGCGCTT CTTGGAGCGGGGGTTGGGCAGAGCGAAGGTGACATCGTTGAAGAGGATTTTGCCCGCGCGGGGCAT GAAGTTGCGGGTGATGCGGAAGGGCCCCGGCACTTCAGAGCGGTTGTTGATGACCTGGGCGGCGAG CACGATCTCGTCGAAGCCGTTGATGTTGTGGCCCACGATGTAGAGTTCCAGGAAGCGGGGCCGGCCC TTTACGGTGGGCAGCTTCTTTAGCTCTTCGTAGGTGAGCTCCTCGGGCGAGGCGAGGCCGTGCTCGGC CAGGGCCCAGTCCGCGAGGTGCGGGTTGTCTCTGAGGAAGGACTTCCAGAGGTCGCGGGCCAGGAG GGTCTGCAGGCGGTCTCTGAAGGTCCTGAACTGGCGGCCCACGGCCATTTTTTCGGGGGTGATGCAG TAGAAGGTGAGGGGGTCTTGCTGCCAGCGGTCCCAGTCGAGCTGCAGGGCGAGGTCGCGCGCGGCG GTGACCAGGCGCTCGTCGCCCCCGAATTTCATGACCAGCATGAAGGGCACGAGCTGCTTTCCGAAGG CCCCCATCCAAGTGTAGGTCTCTACATCGTAGGTGACAAAGAGGCGCTCCGTGCGAGGATGCGAGCC GATCGGGAAGAACTGGATCTCCCGCCACCAGTTGGAGGAGTGGCTGTTGATGTGGTGGAAGTAGAA GTCCCGTCGCCGGGCCGAACACTCGTGCTGGCTTTTGTAAAAGCGAGCGCAGTACTGGCAGCGCTGC ACGGGCTGTACCTCATGCACGAGATGCACCTTTCGCCCGCGCACGAGGAAGCCGAGGGGAAATCTGA GCCCCCCGCCTGGCTCGCGGCATGGCTGGTTCTCTTCTACTTTGGATGCGTGTCCGTCTCCGTCTGGCT CCTCGAGGGGTGTTACGGTGGAGCGGACCACCACGCCGCGCGAGCCGCAGGTCCAGATATCGGCGC GCGGCGGTCGGAGTTTGATGACGACATCGCGCAGCTGGGAGCTGTCCATGGTCTGGAGCTCCCGCGG CGGCGGCAGGTCAGCCGGGAGTTCTTGCAGGTTCACCTCGCAGAGTCGGGCCAGGGCGCGGGGCAG GTCTAGGTGGTACCTGATCTCTAGGGGCGTGTTGGTGGCGGCGTCGATGGCTTGCAGGAGCCCGCAG CCCCGGGGGGCGACGACGGTGCCCCGCGGGGTGGTGGTGGTGGTGGCGGTGCAGCTCAGAAGCGGT GCCGCGGGCGGGCCCCCGGAGGTAGGGGGGGCTCCGGTCCCGCGGGCAGGGGCGGCAGCGGCACGT CGGCGTGGAGCGCGGGCAGGAGTTGGTGCTGTGCCCGGAGGTTGCTGGCGAAGGCGACGACGCGGC GGTTGATCTCCTGGATCTGGCGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCTTGAACCTGAAAGA GAGTTCGACAGAATCAATCTCGGTGTCATTGACCGCGGCCTGGCGCAGGATCTCCTGCACGTCTCCC GAGTTGTCTTGGTAGGCGATCTCGGCCATGAACTGCTCGATCTCTTCCTCCTGGAGGTCTCCGCGTCC GGCGCGTTCCACGGTGGCCGCCAGGTCGTTGGAGATGCGCCCCATGAGCTGCGAGAAGGCGTTGAGT CCGCCCTCGTTCCAGACTCGGCTGTAGACCACGCCCCCCTGGTCATCGCGGGCGCGCATGACCACCT GCGCGAGGTTGAGCTCCACGTGCCGCGCGAAGACGGCGTAGTTGCGCAGACGCTGGAAGAGGTAGT TGAGGGTGGTGGCGGTGTGCTCGGCCACGAAGAAGTTCATGACCCAGCGGCGCAACGTGGATTCGTT GATGTCCCCCAAGGCCTCCAGCCGTTCCATGGCCTCGTAGAAGTCCACGGCGAAGTTGAAAAACTGG GAGTTGCGCGCCGACACGGTCAACTCCTCCTCCAGAAGACGGATGAGCTCGGCGACGGTGTCGCGCA CCTCGCGCTCGAAGGCTATGGGGATCTCTTCCTCCGCTAGCATCACCACCTCCTCCTCTTCCTCCTCTT CTGGCACTTCCATGATGGCTTCCTCCTCTTCGGGGGGTGGCGGCGGCGGCGGTGGGGGAGGGGGCGC TCTGCGCCGGCGGCGGCGCACCGGGAGGCGGTCCACGAAGCGCGCGATCATCTCCCCGCGGCGGCG GCGCATGGTCTCGGTGACGGCGCGGCCGTTCTCCCGGGGGCGCAGTTGGAAGACGCCGCCGGACATC TGGTGCTGGGGCGGGTGGCCGTGAGGCAGCGAGACGGCGCTGACGATGCATCTCAACAATTGCTGCG TAGGTACGCCGCCGAGGGACCTGAGGGAGTCCATATCCACCGGATCCGAAAACCTTTCGAGGAAGG CGTCTAACCAGTCGCAGTCGCAAGGTAGGCTGAGCACCGTGGCGGGCGGCGGGGGGTGGGGGGAGT GTCTGGCGGAGGTGCTGCTGATGATGTAATTGAAGTAGGCGGACTTGACACGGCGGATGGTCGACAG GAGCACCATGTCCTTGGGTCCGGCCTGCTGGATGCGGAGGCGGTCGGCTATGCCCCAGGCTTCGTTCT GGCATCGGCGCAGGTCCTTGTAGTAGTCTTGCATGAGCCTTTCCACCGGCACCTCTTCTCCTTCCTCTT CTGCTTCTTCCATGTCTGCTTCGGCCCTGGGGCGGCGCCGCGCCCCCCTGCCCCCCATGCGCGTGACC CCGAACCCCCTGAGCGGTTGGAGCAGGGCCAGGTCGGCGACGACGCGCTCGGCCAGGATGGCCTGC TGCACCTGCGTGAGGGTGGTTTGGAAGTCATCCAAGTCCACGAAGCGGTGGTAGGCGCCCGTGTTGA TGGTGTAGGTGCAGTTGGCCATGACGGACCAGTTGACGGTCTGGTGGCCCGGTTGCGACATCTCGGT GTACCTGAGTCGCGAGTAGGCGCGGGAGTCGAAGACGTAGTCGTTGCAAGTCCGCACCAGGTACTGG TAGCCCACCAGGAAGTGCGGCGGCGGCTGGCGGTAGAGGGGCCAGCGCAGGGTGGCGGGGGCTCCG GGGGCCAGGTCTTCCAGCATGAGGCGGTGGTAGGCGTAGATGTACCTGGACATCCAGGTGATACCCG CGGCGGTGGTGGAGGCGCGCGGGAAGTCGCGCACCCGGTTCCAGATGTTGCGCAGGGGCAGAAAGT GCTCCATGGTAGGCGTGCTCTGTCCAGTCAGACGCGCGCAGTCGTTGATACTCTAGACCAGGGAAAA CGAAAGCCGGTCAGCGGGCACTCTTCCGTGGTCTGGTGAATAGATCGCAAGGGTATCATGGCGGAGG GCCTCGGTTCGAGCCCCGGGTCCGGGCCGGACGGTCCGCCATGATCCACGCGGTTACCGCCCGCGTG TCGAACCCAGGTGTGCGACGTCAGACAACGGTGGAGTGTTCCTTTTGGCGTTTTTCTGGCCGGGCGCC GGCGCCGCGTAAGAGACTAAGCCGCGAAAGCGAAAGCAGTAAGTGGCTCGCTCCCCGTAGCCGGAG GGATCCTTGCTAAGGGTTGCGTTGCGGCGAACCCCGGTTCGAATCCCGTACTCGGGCCGGCCGGACC CGCGGCTAAGGTGTTGGATTGGCCTCCCCCTCGTATAAAGACCCCGCTTGCGGATTGACTCCGGACA CGGGGACGAGCCCCTTTTATTTTTGCTTTCCCCAGATGCATCCGGTGCTGCGGCAGATGCGCCCCCCG CCCCAGCAGCAGCAACAACACCAGCAAGAGCGGCAGCAACAGCAGCGGGAGTCATGCAGGGCCCCC TCACCCACCCTCGGCGGGCCGGCCACCTCGGCGTCCGCGGCCGTGTCTGGCGCCTGCGGCGGCGGCG GGGGGCCGGCTGACGACCCCGAGGAGCCCCCGCGGCGCAGGGCCAGACACTACCTGGACCTGGAGG AGGGCGAGGGCCTGGCGCGGCTGGGGGCGCCGTCTCCCGAGCGCCACCCGCGGGTGCAGCTGAAGC GCGACTCGCGCGAGGCGTACGTGCCTCGGCAGAACCTGTTCAGGGACCGCGCGGGCGAGGAGCCCG AGGAGATGCGGGACAGGAGGTTCAGCGCAGGGCGGGAGCTGCGGCAGGGGCTGAACCGCGAGCGG CTGCTGCGCGAGGAGGACTTTGAGCCCGACGCGCGGACGGGGATCAGCCCCGCGCGCGCGCACGTG GCGGCCGCCGACCTGGTGACGGCGTACGAGCAGACGGTGAACCAGGAGATCAACTTCCAAAAGAGT TTCAACAACCACGTGCGCACGCTGGTGGCGCGCGAGGAGGTGACCATCGGGCTGATGCACCTGTGGG ACTTTGTAAGCGCGCTGGTGCAGAACCCCAACAGCAAGCCTCTGACGGCGCAGCTGTTCCTGATAGT GCAGCACAGCAGGGACAACGAGGCGTTTAGGGACGCGCTGCTGAACATCACCGAGCCCGAGGGTCG GTGGCTGCTGGACCTGATTAACATCCTGCAGAGCATAGTGGTGCAGGAGCGCAGCCTGAGCCTGGCC GACAAGGTGGCGGCCATCAACTACTCGATGCTGAGCCTGGGCAAGTTTTACGCGCGCAAGATCTACC AGACGCCGTACGTGCCCATAGACAAGGAGGTGAAGATCGACGGTTTTTACATGCGCATGGCGCTGAA GGTGCTCACCCTGAGCGACGACCTGGGCGTGTACCGCAACGAGCGCATCCACAAGGCCGTGAGCGTG AGCCGGCGGCGCGAGCTGAGCGACCGCGAGCTGATGCACAGCCTGCAGCGGGCGCTGGCGGGCGCC GGCAGCGGCGACAGGGAGGCGGAGTCCTACTTCGATGCGGGGGCGGACCTGCGCTGGGCGCCCAGC CGGCGGGCCCTGGAGGCCGCGGGGGTCCGCGAGGACTATGACGAGGACGGCGAGGAGGATGAGGA GTACGAGCTAGAGGAGGGCGAGTACCTGGACTAAACCGCGGGTGGTGTTTCCGGTAGATGCAAGAC CCGAACGTGGTGGACCCGGCGCTGCGGGCGGCTCTGCAGAGCCAGCCGTCCGGCCTTAACTCCTCAG ACGACTGGCGACAGGTCATGGACCGCATCATGTCGCTGACGGCGCGTAACCCGGACGCGTTCCGGCA GCAGCCGCAGGCCAACAGGCTCTCCGCCATCCTGGAGGCGGTGGTGCCTGCGCGCTCGAACCCCACG CACGAGAAGGTGCTGGCCATAGTGAACGCGCTGGCCGAGAACAGGGCCATCCGCCCGGACGAGGCC GGGCTGGTGTACGACGCGCTGCTGCAGCGCGTGGCCCGCTACAACAGCGGCAACGTGCAGACCAAC CTGGACCGGCTGGTGGGGGACGTGCGCGAGGCGGTGGCGCAGCGCGAGCGCGCGGATCGGCAGGGC AACCTGGGCTCCATGGTGGCGCTGAATGCCTTCCTGAGCACGCAGCCGGCCAACGTGCCGCGGGGGC AGGAAGACTACACCAACTTTGTGAGCGCGCTGCGGCTGATGGTGACCGAGACCCCCCAGAGCGAGG TGTACCAGTCGGGCCCGGACTACTTCTTCCAGACCAGCAGACAGGGCCTGCAGACGGTGAACCTGAG CCAGGCTTTCAAGAACCTGCGGGGGCTGTGGGGCGTGAAGGCGCCCACCGGCGACCGGGCGACGGT GTCCAGCCTGCTGACGCCCAACTCGCGCCTGCTGCTGCTGCTGATCGCGCCGTTCACGGACAGCGGC AGCGTGTCCCGGGACACCTACCTGGGGCACCTGCTGACCCTGTACCGCGAGGCCATCGGGCAGGCGC AGGTGGACGAGCACACCTTCCAGGAGATCACCAGCGTGAGCCGCGCGCTGGGGCAGGAGGACACGA GCAGCCTGGAGGCGACTCTGAACTACCTGCTGACCAACCGGCGGCAGAAGATTCCCTCGCTGCACAG CCTGACCTCCGAGGAGGAGCGCATCTTGCGCTACGTGCAGCAGAGCGTGAGCCTGAACCTGATGCGC GACGGGGTGACGCCCAGCGTGGCGCTGGACATGACCGCGCGCAACATGGAACCGGGCATGTACGCC GCGCACCGGCCTTACATCAACCGCCTGATGGACTACCTGCATCGCGCGGCGGCCGTGAACCCCGAGT ACTTTACCAACGCCATCCTGAACCCGCACTGGCTCCCGCCGCCCGGGTTCTACAGCGGGGGCTTCGA GGTCCCGGAGACCAACGATGGCTTCCTGTGGGACGACATGGACGACAGCGTGTTCTCCCCGCGGCCG CAGGCGCTGGCGGAAGCGTCCCTGCTGCGTCCCAAGAAGGAGGAGGAGGAGGAGGCGAGTCGCCGC CGCGGCAGCAGCGGCGTGGCTTCTCTGTCCGAGCTGGGGGCGGCAGCCGCCGCGCGCCCCGGGTCCC TGGGCGGCAGCCCCTTTCCGAGCCTGGTGGGGTCTCTGCACAGCGAGCGCACCACCCGCCCTCGGCT GCTGGGCGAGGACGAGTACCTGAATAACTCCCTGCTGCAGCCGGTGCGGGAGAAAAACCTGCCTCCC GCCTTCCCCAACAACGGGATAGAGAGCCTGGTGGACAAGATGAGCAGATGGAAGACCTATGCGCAG GAGCACAGGGACGCGCCTGCGCTCCGGCCGCCCACGCGGCGCCAGCGCCACGACCGGCAGCGGGGG CTGGTGTGGGATGACGAGGACTCCGCGGACGATAGCAGCGTGCTGGACCTGGGAGGGAGCGGCAAC CCGTTCGCGCACCTGCGCCCCCGCCTGGGGAGGATGTTTTAAAAAAAAAAAAAAAAAGCAAGAAGC ATGATGCAAAAATTAAATAAAACTCACCAAGGCCATGGCGACCGAGCGTTGGTTTCTTGTGTTCCCTT CAGTATGCGGCGCGCGGCGATGTACCAGGAGGGACCTCCTCCCTCTTACGAGAGCGTGGTGGGCGCG GCGGCGGCGGCGCCCTCTTCTCCCTTTGCGTCGCAGCTGCTGGAGCCGCCGTACGTGCCTCCGCGCTA CCTGCGGCCTACGGGGGGGAGAAACAGCATCCGTTACTCGGAGCTGGCGCCCCTGTTCGACACCACC CGGGTGTACCTGGTGGACAACAAGTCGGCGGACGTGGCCTCCCTGAACTACCAGAACGACCACAGC AATTTTTTGACCACGGTCATCCAGAACAATGACTACAGCCCGAGCGAGGCCAGCACCCAGACCATCA ATCTGGATGACCGGTCGCACTGGGGCGGCGACCTGAAAACCATCCTGCACACCAACATGCCCAACGT GAACGAGTTCATGTTCACCAATAAGTTCAAGGCGCGGGTGATGGTGTCGCGCTCGCACACCAAGGAA GACCGGGTGGAGCTGAAGTACGAGTGGGTGGAGTTCGAGCTGCCAGAGGGCAACTACTCCGAGACC ATGACCATTGACCTGATGAACAACGCGATCGTGGAGCACTATCTGAAAGTGGGCAGGCAGAACGGG GTCCTGGAGAGCGACATCGGGGTCAAGTTCGACACCAGGAACTTCCGCCTGGGGCTGGACCCCGTGA CCGGGCTGGTTATGCCCGGGGTGTACACCAACGAGGCCTTCCATCCCGACATCATCCTGCTGCCCGG CTGCGGGGTGGACTTCACTTACAGCCGCCTGAGCAACCTCCTGGGCATCCGCAAGCGGCAGCCCTTC CAGGAGGGCTTCAGGATCACCTACGAGGACCTGGAGGGGGGCAACATCCCCGCGCTCCTCGATGTGG AGGCCTACCAGGATAGCTTGAAGGAAAATGAGGCGGGACAGGAGGATACCGCCCCCGCCGCCTCCG CCGCCGCCGAGCAGGGCGAGGATGCTGCTGACACCGCGGCCGCGGACGGGGCAGAGGCCGACCCCG CTATGGTGGTGGAGGCTCCCGAGCAGGAGGAGGACATGAATGACAGTGCGGTGCGCGGAGACACCT TCGTCACCCGGGGGGAGGAAAAGCAAGCGGAGGCCGAGGCCGCGGCCGAGGAAAAGCAACTGGCG GCAGCAGCGGCGGCGGCGGCGTTGGCCGCGGCGGAGGCTGAGTCTGAGGGGACCAAGCCCGCCAAG GAGCCCGTGATTAAGCCCCTGACCGAAGATAGCAAGAAGCGCAGTTACAACCTGCTCAAGGACAGC ACCAACACCGCGTACCGCAGCTGGTACCTGGCCTACAACTACGGCGACCCGTCGACGGGGGTGCGCT CCTGGACCCTGCTGTGCACGCCGGACGTGACCTGCGGCTCGGAGCAGGTGTACTGGTCGCTGCCCGA CATGATGCAAGACCCCGTGACCTTCCGCTCCACGCGGCAGGTCAGCAACTTCCCGGTGGTGGGCGCC GAGCTGCTGCCCGTGCACTCCAAGAGCTTCTACAACGACCAGGCCGTCTACTCCCAGCTCATCCGCC AGTTCACCTCTCTGACCCACGTGTTCAATCGCTTTCCTGAGAACCAGATTCTGGCGCGCCCGCCCGCC CCCACCATCACCACCGTCAGTGAAAACGTTCCTGCTCTCACAGATCACGGGACGCTACCGCTGCGCA ACAGCATCGGAGGAGTCCAGCGAGTGACCGTTACTGACGCCAGACGCCGCACCTGCCCCTACGTTTA CAAGGCCTTGGGCATAGTCTCGCCGCGCGTCCTTTCCAGCCGCACTTTTTGAGCAACACCACCATCAT GTCCATCCTGATCTCACCCAGCAATAACTCCGGCTGGGGACTGCTGCGCGCGCCCAGCAAGATGTTC GGAGGGGCGAGGAAGCGTTCCGAGCAGCACCCCGTGCGCGTGCGCGGGCACTTCCGCGCCCCCTGG GGAGCGCACAAACGCGGCCGCGCGGGGCGCACCACCGTGGACGACGCCATCGACTCGGTGGTGGAG CAGGCGCGCAACTACAGGCCCGCGGTCTCTACCGTGGACGCGGCCATCCAGACCGTGGTGCGGGGCG CGCGGCGGTACGCCAAGCTGAAGAGCCGCCGGAAGCGCGTGGCCCGCCGCCACCGCCGCCGACCCG GGGCCGCCGCCAAACGCGCCGCCGCGGCCCTGCTTCGCCGGGCCAAGCGCACGGGCCGCCGCGCCG CCATGAGGGCCGCGCGCCGCTTGGCCGCCGGCATCACCGCCGCCACCATGGCCCCCCGTACCCGAAG ACGCGCGGCCGCCGCCGCCGCCGCCGCCATCAGTGACATGGCCAGCAGGCGCCGGGGCAACGTGTA CTGGGTGCGCGACTCGGTGACCGGCACGCGCGTGCCCGTGCGCTTCCGCCCCCCGCGGACTTGAGAT GATGTGAAAAAACAACACTGAGTCTCCTGCTGTTGTGTGTATCCCAGCGGCGGCGGCGCGCGCAGCG TCATGTCCAAGCGCAAAATCAAAGAAGAGATGCTCCAGGTCGTCGCGCCGGAGATCTATGGGCCCCC GAAGAAGGAAGAGCAGGATTCGAAGCCCCGCAAGATAAAGCGGGTCAAAAAGAAAAAGAAAGATG ATGACGATGCCGATGGGGAGGTGGAGTTCCTGCGCGCCACGGCGCCCAGGCGCCCGGTGCAGTGGA AGGGCCGGCGCGTAAAGCGCGTCCTGCGCCCCGGCACCGCGGTGGTCTTCACGCCCGGCGAGCGCTC CACCCGGACTTTCAAGCGCGTCTATGACGAGGTGTACGGCGACGAAGACCTGCTGGAGCAGGCCAAC GAGCGCTTCGGAGAGTTTGCTTACGGGAAGCGTCAGCGGGCGCTGGGGAAGGAGGACCTGCTGGCG CTGCCGCTGGACCAGGGCAACCCCACCCCCAGTCTGAAGCCCGTGACCCTGCAGCAGGTGCTGCCGA GCAGCGCACCCTCCGAGGCGAAGCGGGGTCTGAAGCGCGAGGGCGGCGACCTGGCGCCCACCGTGC AGCTCATGGTGCCCAAGCGGCAGAGGCTGGAGGATGTGCTGGAGAAAATGAAAGTAGACCCCGGTC TGCAGCCGGACATCAGGGTCCGCCCCATCAAGCAGGTGGCGCCGGGCCTCGGCGTGCAGACCGTGG ACGTGGTCATCCCCACCGGCAACTCCCCCGCCGCCGCCACCACTACCGCTGCCTCCACGGACATGGA GACACAGACCGATCCCGCCGCAGCCGCAGCCGCAGCCGCCGCCGCGACCTCCTCGGCGGAGGTGCA GACGGACCCCTGGCTGCCGCCGGCGATGTCAGCTCCCCGCGCGCGTCGCGGGCGCAGGAAGTACGGC GCCGCCAACGCGCTCCTGCCCGAGTACGCCTTGCATCCTTCCATCGCGCCCACCCCCGGCTACCGAGG CTATACCTACCGCCCGCGAAGAGCCAAGGGTTCCACCCGCCGTCCCCGCCGACGCGCCGCCGCCACC ACCCGCCGCCGCCGCCGCAGACGCCAGCCCGCACTGGCTCCAGTCTCCGTGAGGAAAGTGGCGCGCG ACGGACACACCCTGGTGCTGCCCAGGGCGCGCTACCACCCCAGCATCGTTTAAAAGCCTGTTGTGGT TCTTGCAGATATGGCCCTCACTTGCCGCCTCCGTTTCCCGGTGCCGGGATACCGAGGAGGAAGATCG CGCCGCAGGAGGGGTCTGGCCGGCCGCGGCCTGAGCGGAGGCAGCCGCCGCGCGCACCGGCGGCGA CGCGCCACCAGCCGACGCATGCGCGGCGGGGTGCTGCCCCTGTTAATCCCCCTGATCGCCGCGGCGA TCGGCGCCGTGCCCGGGATCGCCTCCGTGGCCTTGCAAGCGTCCCAGAGGCATTGACAGACTTGCAA ACTTGCAAATATGGAAAAAAAAACCCCAATAAAAAAGTCTAGACTCTCACGCTCGCTTGGTCCTGTG ACTATTTTGTAGAATGGAAGACATCAACTTTGCGTCGCTGGCCCCGCGTCACGGCTCGCGCCCGTTCC TGGGACACTGGAACGATATCGGCACCAGCAACATGAGCGGTGGCGCCTTCAGTTGGGGCTCTCTGTG GAGCGGCATTAAAAGTATCGGGTCTGCCGTTAAAAATTACGGCTCCCGGGCCTGGAACAGCAGCACG GGCCAGATGTTGAGAGACAAGTTGAAAGAGCAGAACTTCCAGCAGAAGGTGGTGGAGGGCCTGGCC TCCGGCATCAACGGGGTGGTGGACCTGGCCAACCAGGCCGTGCAGAATAAGATCAACAGCAGACTG GACCCCCGGCCGCCGGTGGAGGAGGTGCCGCCGGCGCTGGAGACGGTGTCCCCCGATGGGCGTGGC GAGAAGCGCCCGCGGCCCGATAGGGAAGAGACCACTCTGGTCACGCAGACCGATGAGCCGCCCCCG TATGAGGAGGCCCTGAAGCAAGGTCTGCCCACCACGCGGCCCATCGCGCCCATGGCCACCGGGGTGG TGGGCCGCCACACCCCCGCCACGCTGGACTTGCCTCCGCCCGCCGATGTGCCGCAGCAGCAGAAGGC GGCACAGCCGGGCCCGCCCGCGACCGCCTCCCGTTCCTCCGCCGGTCCTCTGCGCCGCGCGGCCAGC GGCCCCCGCGGGGGGGTCGCGAGGCACGGCAACTGGCAGAGCACGCTGAACAGCATCGTGGGTCTG GGGGTGCGGTCCGTGAAGCGCCGCCGATGCTACTGAATAGCTTAGCTAACGTGTTGTATGTGTGTAT GCGCCCTATGTCGCCGCCAGAGGAGCTGCTGAGTCGCCGCCGTTCGCGCGCCCACCACCACCGCCAC TCCGCCCCTCAAGATGGCGACCCCATCGATGATGCCGCAGTGGTCGTACATGCACATCTCGGGCCAG GACGCCTCGGAGTACCTGAGCCCCGGGCTGGTGCAGTTCGCCCGCGCCACCGAGAGCTACTTCAGCC TGAGTAACAAGTTTAGGAACCCCACGGTGGCGCCCACGCACGATGTGACCACCGACCGGTCTCAGCG CCTGACGCTGCGGTTCATTCCCGTGGACCGCGAGGACACCGCGTACTCGTACAAGGCGCGGTTCACC CTGGCCGTGGGCGACAACCGCGTGCTGGACATGGCCTCCACCTACTTTGACATCCGCGGGGTGCTGG ACCGGGGTCCCACTTTCAAGCCCTACTCTGGCACCGCCTACAACTCCCTGGCCCCCAAGGGCGCTCCC AACTCCTGCGAGTGGGAGCAAGAGGAAACTCAGGCAGTTGAAGAAGCAGCAGAAGAGGAAGAAGA AGATGCTGACGGTCAAGCTGAGGAAGAGCAAGCAGCTACCAAAAAGACTCATGTATATGCTCAGGC TCCCCTTTCTGGCGAAAAAATTAGTAAAGATGGTCTGCAAATAGGAACGGACGCTACAGCTACAGAA CAAAAACCTATTTATGCAGACCCTACATTCCAGCCCGAACCCCAAATCGGGGAGTCCCAGTGGAATG AGGCAGATGCTACAGTCGCCGGCGGTAGAGTGCTAAAGAAATCTACTCCCATGAAACCATGCTATGG TTCCTATGCAAGACCCACAAATGCTAATGGAGGTCAGGGTGTACTAACGGCAAATGCCCAGGGACAG CTAGAATCTCAGGTTGAAATGCAATTCTTTTCAACTTCTGAAAACGCCCGTAACGAGGCTAACAACA TTCAGCCCAAATTGGTGCTGTATAGTGAGGATGTGCACATGGAGACCCCGGATACGCACCTTTCTTAC AAGCCCGCAAAAAGCGATGACAATTCAAAAATCATGCTGGGTCAGCAGTCCATGCCCAACAGACCT AATTACATCGGCTTCAGAGACAACTTTATCGGCCTCATGTATTACAATAGCACTGGCAACATGGGAG TGCTTGCAGGTCAGGCCTCTCAGTTGAATGCAGTGGTGGACTTGCAAGACAGAAACACAGAACTGTC CTACCAGCTCTTGCTTGATTCCATGGGTGACAGAACCAGATACTTTTCCATGTGGAATCAGGCAGTGG ACAGTTATGACCCAGATGTTAGAATTATTGAAAATCATGGAACTGAAGACGAGCTCCCCAACTATTG TTTCCCTCTGGGTGGCATAGGGGTAACTGACACTTACCAGGCTGTTAAAACCAACAATGGCAATAAC GGGGGCCAGGTGACTTGGACAAAAGATGAAACTTTTGCAGATCGCAATGAAATAGGGGTGGGAAAC AATTTCGCTATGGAGATCAACCTCAGTGCCAACCTGTGGAGAAACTTCCTGTACTCCAACGTGGCGCT GTACCTACCAGACAAGCTTAAGTACAACCCCTCCAATGTGGACATCTCTGACAACCCCAACACCTAC GATTACATGAACAAGCGAGTGGTGGCCCCGGGGCTGGTGGACTGCTACATCAACCTGGGCGCGCGCT GGTCGCTGGACTACATGGACAACGTCAACCCCTTCAACCACCACCGCAATGCGGGCCTGCGCTACCG CTCCATGCTCCTGGGCAACGGGCGCTACGTGCCCTTCCACATCCAGGTGCCCCAGAAGTTCTTTGCCA TCAAGAACCTCCTCCTCCTGCCGGGCTCCTACACCTACGAGTGGAACTTCAGGAAGGATGTCAACAT GGTCCTCCAGAGCTCTCTGGGTAACGATCTCAGGGTGGACGGGGCCAGCATCAAGTTCGAGAGCATC TGCCTCTACGCCACCTTCTTCCCCATGGCCCACAACACGGCCTCCACGCTCGAGGCCATGCTCAGGAA CGACACCAACGACCAGTCCTTCAATGACTACCTCTCCGCCGCCAACATGCTCTACCCCATACCCGCCA ACGCCACCAACGTCCCCATCTCCATCCCCTCGCGCAACTGGGCGGCCTTCCGCGGCTGGGCCTTCACC CGCCTCAAGACCAAGGAGACCCCCTCCCTGGGCTCGGGATTCGACCCCTACTACACCTACTCGGGCT CCATTCCCTACCTGGACGGCACCTTCTACCTCAACCACACTTTCAAGAAGGTCTCGGTCACCTTCGAC TCCTCGGTCAGCTGGCCGGGCAACGACCGTCTGCTCACCCCCAACGAGTTCGAGATCAAGCGCTCGG TCGACGGGGAGGGCTACAACGTGGCCCAGTGCAACATGACCAAGGACTGGTTCCTGGTCCAGATGCT GGCCAACTACAACATCGGCTACCAGGGCTTCTACATCCCAGAGAGCTACAAGGACAGGATGTACTCC TTCTTCAGGAACTTCCAGCCCATGAGCCGGCAGGTGGTGGACCAGACCAAGTACAAGGACTACCAGG AGGTGGGCATCATCCACCAGCACAACAACTCGGGCTTCGTGGGCTACCTCGCCCCCACCATGCGCGA GGGACAGGCCTACCCCGCCAACTTCCCCTATCCGCTCATAGGCAAGACCGCGGTCGACAGCATCACC CAGAAAAAGTTCCTCTGCGACCGCACCCTCTGGCGCATCCCCTTCTCCAGCAACTTCATGTCCATGGG TGCGCTCTCGGACCTGGGCCAGAACTTGCTCTACGCCAACTCCGCCCACGCCCTCGACATGACCTTCG AGGTCGACCCCATGGACGAGCCCACCCTTCTCTATGTTCTGTTCGAAGTCTTTGACGTGGTCCGGGTC CACCAGCCGCACCGCGGCGTCATCGAGACCGTGTACCTGCGTACGCCCTTCTCGGCCGGCAACGCCA CCACCTAAAGAAGCAAGCCGCAGTCATCGCCGCCTGCATGCCGTCGGGTTCCACCGAGCAAGAGCTC AGGGCCATCGTCAGAGACCTGGGATGCGGGCCCTATTTTTTGGGCACCTTCGACAAGCGCTTCCCTG GCTTTGTCTCCCCACACAAGCTGGCCTGCGCCATCGTCAACACGGCCGGCCGCGAGACCGGGGGCGT GCACTGGCTGGCCTTCGCCTGGAACCCGCGCTCCAAAACATGCTTCCTCTTTGACCCCTTCGGCTTTT CGGACCAGCGGCTCAAGCAAATCTACGAGTTCGAGTACGAGGGCTTGCTGCGTCGCAGCGCCATCGC CTCCTCGCCCGACCGCTGCGTCACCCTCGAAAAGTCCACCCAGACCGTGCAGGGGCCCGACTCGGCC GCCTGCGGTCTCTTCTGCTGCATGTTTCTGCACGCCTTTGTGCACTGGCCTCAGAGTCCCATGGACCG CAACCCCACCATGAACTTGCTGACGGGGGTGCCCAACTCCATGCTCCAGAGCCCCCAGGTCGAGCCC ACCCTGCGCCGCAACCAGGAGCAGCTCTACAGCTTCCTGGAGCGCCACTCGCCTTACTTCCGCCGCC ACAGCGCACAGATCAGGAGGGCCACCTCCTTCTGCCACTTGCAAGAGATGCAAGAAGGGTAATAAC GATGTACACACTTTTTTTCTCAATAAATGGCATCTTTTTATTTATACAAGCTCTCTGGGGTATTCATTT CCCACCACCACCCGCCGTTGTCGCCATCTGGCTCTATTTAGAAATCGAAAGGGTTCTGCCGGGAGTCG CCGTGCGCCACGGGCAGGGACACGTTGCGATACTGGTAGCGGGTGCCCCACTTGAACTCGGGCACCA CCAGGCGAGGCAGCTCGGGGAAGTTTTCGCTCCACAGGCTGCGGGTCAGCACCAGCGCGTTCATCAG GTCGGGCGCCGAGATCTTGAAGTCGCAGTTGGGGCCGCCGCCCTGCGCGCGCGAGTTGCGGTACACC GGGTTGCAGCACTGGAACACCAACAGCGCCGGGTGCTTCACGCTGGCCAGCACGCTGCGGTCGGAG ATCAGCTCGGCGTCCAGGTCCTCCGCGTTGCTCAGCGCGAACGGGGTCATCTTGGGCACTTGCCGCCC CAGGAAGGGCGCGTGCCCCGGTTTCGAGTTGCAGTCGCAGCGCAGCGGGATCAGCAGGTGCCCGTGC CCGGACTCGGCGTTGGGGTACAGCGCGCGCATGAAGGCCTGCATCTGGCGGAAGGCCATCTGGGCCT TGGCGCCCTCCGAGAAGAACATGCCGCAGGACTTGCCCGAGAACTGGTTTGCGGGGCAGCTGGCGTC GTGCAGGCAGCAGCGCGCGTCGGTGTTGGCGATCTGCACCACGTTGCGCCCCCACCGGTTCTTCACG ATCTTGGCCTTGGACGATTGCTCCTTCAGCGCGCGCTGCCCGTTCTCGCTGGTCACATCCATCTCGAT CACATGTTCCTTGTTCACCATGCTGCTGCCGTGCAGACACTTCAGCTCGCCCTCCGTCTCGGTGCAGC GGTGCTGCCACAGCGCGCAGCCCGTGGGCTCGAAAGACTTGTAGGTCACCTCCGCGAAGGACTGCAG GTACCCCTGCAAAAAGCGGCCCATCATGGTCACGAAGGTCTTGTTGCTGCTGAAGGTCAGCTGCAGC CCGCGGTGCTCCTCGTTCAGCCAGGTCTTGCACACGGCCGCCAGCGCCTCCACCTGGTCGGGCAGCA TCTTGAAGTTCACCTTCAGCTCATTCTCCACGTGGTACTTGTCCATCAGCGTGCGCGCCGCCTCCATG CCCTTCTCCCAGGCCGACACCAGCGGCAGGCTCACGGGGTTCTTCACCATCACCGTGGCCGCCGCCTC CGCCGCGCTTTCGCTTTCCGCCCCGCTGTTCTCTTCCTCTTCCTCCTCTTCCTCGCCGCCGCCCACTCGC AGCCCCCGCACCACGGGGTCGTCTTCCTGCAGGCGCTGCACCTTGCGCTTGCCGTTGCGCCCCTGCTT GATGCGCACGGGCGGGTTGCTGAAGCCCACCATCACCAGCGCGGCCTCTTCTTGCTCGTCCTCGCTGT CCAGAATGACCTCCGGGGAGGGGGGGTTGGTCATCCTCAGTACCGAGGCACGCTTCTTTTTCTTCCTG GGGGCGTTCGCCAGCTCCGCGGCTGCGGCCGCTGCCGAGGTCGAAGGCCGAGGGCTGGGCGTGCGC GGCACCAGCGCGTCCTGCGAGCCGTCCTCGTCCTCCTCGGACTCGAGACGGAGGCGGGCCCGCTTCT TCGGGGGCGCGCGGGGCGGCGGAGGCGGCGGCGGCGACGGAGACGGGGACGAGACATCGTCCAGG GTGGGTGGACGGCGGGCCGCGCCGCGTCCGCGCTCGGGGGTGGTCTCGCGCTGGTCCTCTTCCCGAC TGGCCATCTCCCACTGCTCCTTCTCCTATAGGCAGAAAGAGATCATGGAGTCTCTCATGCGAGTCGAG AAGGAGGAGGACAGCCTAACCGCCCCCTCTGAGCCCTCCACCACCGCCGCCACCACCGCCAATGCCG CCGCGGACGACGCGCCCACCGAGACCACCGCCAGTACCACCCTCCCCAGCGACGCACCCCCGCTCGA GAATGAAGTGCTGATCGAGCAGGACCCGGGTTTTGTGAGCGGAGAGGAGGATGAGGTGGATGAGAA GGAGAAGGAGGAGGTCGCCGCCTCAGTGCCAAAAGAGGATAAAAAGCAAGACCAGGACGACGCAG ATAAGGATGAGACAGCAGTCGGGCGGGGGAACGGAAGCCATGATGCTGATGACGGCTACCTAGACG TGGGAGACGACGTGCTGCTTAAGCACCTGCACCGCCAGTGCGTCATCGTCTGCGACGCGCTGCAGGA GCGCTGCGAAGTGCCCCTGGACGTGGCGGAGGTCAGCCGCGCCTACGAGCGGCACCTCTTCGCGCCG CACGTGCCCCCCAAGCGCCGGGAGAACGGCACCTGCGAGCCCAACCCGCGTCTCAACTTCTACCCGG TCTTCGCGGTACCCGAGGTGCTGGCCACCTACCACATCTTTTTCCAAAACTGCAAGATCCCCCTCTCC TGCCGCGCCAACCGCACCCGCGCCGACAAAACCCTGACCCTGCGGCAGGGCGCCCACATACCTGATA TCGCCTCTCTGGAGGAAGTGCCCAAGATCTTCGAGGGTCTCGGTCGCGACGAGAAACGGGCGGCGAA CGCTCTGCACGGAGACAGCGAAAACGAGAGTCACTCGGGGGTGCTGGTGGAGCTCGAGGGCGACAA CGCGCGCCTGGCCGTACTCAAGCGCAGCATAGAGGTCACCCACTTTGCCTACCCGGCGCTCAACCTG CCCCCCAAGGTCATGAGTGTGGTCATGGGCGAGCTCATCATGCGCCGCGCCCAGCCCCTGGCCGCGG ATGCAAACTTGCAAGAGTCCTCCGAGGAAGGCCTGCCCGCGGTCAGCGACGAGCAGCTGGCGCGCT GGCTGGAGACCCGCGACCCCGCGCAGCTGGAGGAGCGGCGCAAGCTCATGATGGCCGCGGTGCTGG TCACCGTGGAGCTCGAGTGTCTGCAGCGCTTCTTCGCGGACCCCGAGATGCAGCGCAAGCTCGAGGA GACCCTGCACTACACCTTCCGCCAGGGCTACGTGCGCCAGGCCTGCAAGATCTCCAACGTGGAGCTC TGCAACCTGGTCTCCTACCTGGGCATCCTGCACGAGAACCGCCTCGGGCAGAACGTCCTGCACTCCA CCCTCAAAGGGGAGGCGCGCCGCGACTACATCCGCGACTGCGCCTACCTCTTCCTCTGCTACACCTG GCAGACGGCCATGGGGGTCTGGCAGCAGTGCCTGGAGGAGCGCAACCTCAAGGAGCTGGAAAAGCT CCTCAAGCGCACCCTCAGGGACCTCTGGACGGGCTTCAACGAGCGCTCGGTGGCCGCCGCGCTGGCG GACATCATCTTTCCCGAGCGCCTGCTCAAGACCCTGCAGCAGGGCCTGCCCGACTTCACCAGCCAGA GCATGCTGCAGAACTTCAGGACTTTCATCCTGGAGCGCTCGGGCATCCTGCCGGCCACTTGCTGCGCG CTGCCCAGCGACTTCGTGCCCATCAAGTACAGGGAGTGCCCGCCGCCGCTCTGGGGCCACTGCTACC TCTTCCAGCTGGCCAACTACCTCGCCTACCACTCGGACCTCATGGAAGACGTGAGCGGCGAGGGCCT GCTCGAGTGCCACTGCCGCTGCAACCTCTGCACGCCCCACCGCTCTCTAGTCTGCAACCCGCAGCTGC TCAGCGAGAGTCAGATTATCGGTACCTTCGAGCTGCAGGGTCCCTCGCCTGACGAGAAGTCCGCGGC TCCAGGGCTGAAACTCACTCCGGGGCTGTGGACTTCCGCCTACCTACGCAAATTTGTACCTGAGGACT ACCACGCCCACGAGATCAGGTTCTACGAAGACCAATCCCGCCCGCCCAAGGCGGAGCTCACCGCCTG CGTCATCACCCAGGGGCACATCCTGGGCCAATTGCAAGCCATCAACAAAGCCCGCCGAGAGTTCTTG CTGAAAAAGGGTCGGGGGGTGTACCTGGACCCCCAGTCCGGCGAGGAGCTAAACCCGCTACCCCCG CCGCCGCCCCAGCAGCGGGACCTTGCTTCCCAGGATGGCACCCAGAAAGAAGCAGCAGCCGCCGCC GCCGCCGCAGCCATACATGCTTCTGGAGGAAGAGGAGGAGGACTGGGACAGTCAGGCAGAGGAGGT TTCGGACGAGGAGCAGGAGGAGATGATGGAAGACTGGGAGGAGGACAGCAGCCTAGACGAGGAAG CTTCAGAGGCCGAAGAGGTGGCAGACGCAACACCATCGCCCTCGGTCGCAGCCCCCTCGCCGGGGCC CCTGAAATCCTCCGAACCCAGCACCAGCGCTATAACCTCCGCTCCTCCGGCGCCGGCGCCACCCGCC CGCAGACCCAACCGTAGATGGGACACCACAGGAACCGGGGTCGGTAAGTCCAAGTGCCCGCCGCCG CCACCGCAGCAGCAGCAGCAGCAGCGCCAGGGCTACCGCTCGTGGCGCGGGCACAAGAACGCCATA GTCGCCTGCTTGCAAGACTGCGGGGGCAACATCTCTTTCGCCCGCCGCTTCCTGCTATTCCACCACGG GGTCGCCTTTCCCCGCAATGTCCTGCATTACTACCGTCATCTCTACAGCCCCTACTGCAGCGGCGACC CAGAGGCGGCAGCGGCAGCCACAGCGGCGACCACCACCTAGGAAGATATCCTCCGCGGGCAAGACA GCGGCAGCAGCGGCCAGGAGACCCGCGGCAGCAGCGGCGGGAGCGGTGGGCGCACTGCGCCTCTCG CCCAACGAACCCCTCTCGACCCGGGAGCTCAGACACAGGATCTTCCCCACTTTGTATGCCATCTTCCA ACAGAGCAGAGGCCAGGAGCAGGAGCTGAAAATAAAAAACAGATCTCTGCGCTCCCTCACCCGCAG CTGTCTGTATCACAAAAGCGAAGATCAGCTTCGGCGCACGCTGGAGGACGCGGAGGCACTCTTCAGC AAATACTGCGCGCTCACTCTTAAAGACTAGCTCCGCGCCCTTCTCGAATTTAGGCGGGAGAAAACTA CGTCATCGCCGGCCGCCGCCCAGCCCGCCCAGCCGAGATGAGCAAAGAGATTCCCACGCCATACATG TGGAGCTACCAGCCGCAGATGGGACTCGCGGCGGGAGCGGCCCAGGACTACTCCACCCGCATGAAC TACATGAGCGCGGGACCCCACATGATCTCACAGGTCAACGGGATCCGCGCCCAGCGAAACCAAATA CTGCTGGAACAGGCGGCCATCACCGCCACGCCCCGCCATAATCTCAACCCCCGAAATTGGCCCGCCG CCCTCGTGTACCAGGAAACCCCCTCCGCCACCACCGTACTACTTCCGCGTGACGCCCAGGCCGAAGT CCAGATGACTAACTCAGGGGCGCAGCTCGCGGGCGGCTTTCGTCACGGGGCGCGGCCGCTCCGACCA GGTATAAGACACCTGATGATCAGAGGCCGAGGTATCCAGCTCAACGACGAGTCGGTGAGCTCTTCGC TCGGTCTCCGTCCGGACGGAACTTTCCAGCTCGCCGGATCCGGCCGCTCTTCGTTCACGCCCCGCCAG GCGTACCTGACTCTGCAGACCTCGTCCTCGGAGCCCCGCTCCGGCGGCATCGGAACCCTCCAGTTCGT GGAGGAGTTCGTGCCCTCGGTCTACTTCAACCCCTTCTCGGGACCTCCCGGACGCTACCCCGACCAGT TCATTCCGAACTTTGACGCGGTGAAGGACTCGGCGGACGGCTACGACTGAATGTCAGGTGTCGAGGC AGAGCAGCTTCGCCTGAGACACCTCGAGCACTGCCGCCGCCACAAGTGCTTCGCCCGCGGTTCTGGT GAGTTCTGCTACTTTCAGCTACCCGAGGAGCATACCGAGGGGCCGGCGCACGGCGTCCGCCTGACCA CCCAGGGCGAGGTTACCTGTTCCCTCATCCGGGAGTTTACCCTCCGTCCCCTGCTAGTGGAGCGGGAG CGGGGTCCCTGTGTCCTAACTATCGCCTGCAACTGCCCTAACCCTGGATTACATCAAGATCTTTGCTG TCATCTCTGTGCTGAGTTTAATAAACGCTGAGATCAGAATCTACTGGGGCTCCTGTCGCCATCCTGTG AACGCCACCGTCTTCACCCACCCCGACCAGGCCCAGGCGAACCTCACCTGCGGTCTGCATCGGAGGG CCAAGAAGTACCTCACCTGGTACTTCAACGGCACCCCCTTTGTGGTTTACAACAGCTTCGACGGGGA CGGAGTCTCCCTGAAAGACCAGCTCTCCGGTCTCAGCTACTCCATCCACAAGAACACCACCCTCCAA CTCTTCCCTCCCTACCTGCCGGGAACCTACGAGTGCGTCACCGGCCGCTGCACCCACCTCACCCGCCT GATCGTAAACCAGAGCTTTCCGGGAACAGATAACTCCCTCTTCCCCAGAACAGGAGGTGAGCTCAGG AAACTCCCCGGGGACCAGGGCGGAGACGTACCTTCGACCCTTGTGGGGTTAGGATTTTTTATTACCG GGTTGCTGGCTCTTTTAATCAAAGTTTCCTTGAGATTTGTTCTTTCCTTCTACGTGTATGAACACCTCA ACCTCCAATAACTCTACCCTTTCTTCGGAATCAGGTGACTTCTCTGAAATCGGGCTTGGTGTGCTGCT TACTCTGTTGATTTTTTTCCTTATCATACTCAGCCTTCTGTGCCTCAGGCTCGCCGCCTGCTGCGCACA CATCTATATCTACTGCTGGTTGCTCAAGTGCAGGGGTCGCCACCCAAGATGAACAGGTACATGGTCC TATCGATCCTAGGCCTGCTGGCCCTGGCGGCCTGCAGCGCCGCCAAAAAAGAGATTACCTTTGAGGA GCCCGCTTGCAATGTAACTTTCAAGCCCGAGGGTGACCAATGCACCACCCTCGTCAAATGCGTTACC AATCATGAGAGGCTGCGCATCGACTACAAAAACAAAACTGGCCAGTTTGCGGTCTATAGTGTGTTTA CGCCCGGAGACCCCTCTAACTACTCTGTCACCGTCTTCCAGGGCGGACAGTCTAAGATATTCAATTAC ACTTTCCCTTTTTATGAGTTATGCGATGCGGTCATGTACATGTCAAAACAGTACAACCTGTGGCCTCC CTCTCCCCAGGCGTGTGTGGAAAATACTGGGTCTTACTGCTGTATGGCTTTCGCAATCACTACGCTCG CTCTAATCTGCACGGTGCTATACATAAAATTCAGGCAGAGGCGAATCTTTATCGATGAAAAGAAAAT GCCTTGATCGCTAACACCGGCTTTCTATCTGCAGAATGAATGCAATCACCTCCCTACTAATCACCACC ACCCTCCTTGCGATTGCCCATGGGTTGACACGAATCGAAGTGCCAGTGGGGTCCAATGTCACCATGG TGGGCCCCGCCGGCAATTCCACCCTCATGTGGGAAAAATTTGTCCGCAATCAATGGGTTCATTTCTGC TCTAACCGAATCAGTATCAAGCCCAGAGCCATCTGCGATGGGCAAAATCTAACTCTGATCAATGTGC AAATGATGGATGCTGGGTACTATTACGGGCAGCGGGGAGAAATCATTAATTACTGGCGACCCCACAA GGACTACATGCTGCATGTAGTCGAGGCACTTCCCACTACCACCCCCACTACCACCTCTCCCACCACCA CCACCACTACTACTACTACTACTACTACTACTACTACTACCACTACCGCTGCCCGCCATACCCGCAAA AGCACCATGATTAGCACAAAGCCCCCTCGTGCTCACTCCCACGCCGGCGGGCCCATCGGTGCGACCT CAGAAACCACCGAGCTTTGCTTCTGCCAATGCACTAACGCCAGCGCTCATGAACTGTTCGACCTGGA GAATGAGGATGTCCAGCAGAGCTCCGCTTGCCTGACCCAGGAGGCTGTGGAGCCCGTTGCCCTGAAG CAGATCGGTGATTCAATAATTGACTCTTCTTCTTTTGCCACTCCCGAATACCCTCCCGATTCTACTTTC CACATCACGGGTACCAAAGACCCTAACCTCTCTTTCTACCTGATGCTGCTGCTCTGTATCTCTGTGGT CTCTTCCGCGCTGATGTTACTGGGGATGTTCTGCTGCCTGATCTGCCGCAGAAAGAGAAAAGCTCGCT CTCAGGGCCAACCACTGATGCCCTTCCCCTACCCCCCGGATTTTGCAGATAACAAGATATGAGCTCGC TGCTGACACTAACCGCTTTACTAGCCTGCGCTCTAACCCTTGTCGCTTGCGACTCGAGATTCCACAAT GTCACAGCTGTGGCAGGAGAAAATGTTACTTTCAACTCCACGGCCGATACCCAGTGGTCGTGGAGTG GCTCAGGTAGCTACTTAACTATCTGCAATAGCTCCACTTCCCCCGGCATATCCCCAACCAAGTACCAA TGCAATGCCAGCCTGTTCACCCTCATCAACGCTTCCACCCTGGACAATGGACTCTATGTAGGCTATGT ACCCTTTGGTGGGCAAGGAAAGACCCACGCTTACAACCTGGAAGTTCGCCAGCCCAGAACCACTACC CAAGCTTCTCCCACCACCACCACCACCACCACCATCACCAGCAGCAGCAGCAGCAGCAGCCACAGCA GCAGCAGCAGATTATTGACTTTGGTTTTGGCCAGCTCATCTGCCGCTACCCAGGCCATCTACAGCTCT GTGCCCGAAACCACTCAGATCCACCGCCCAGAAACGACCACCGCCACCACCCTACACACCTCCAGCG ATCAGATGCCGACCAACATCACCCCCTTGGCTCTTCAAATGGGACTTACAAGCCCCACTCCAAAACC AGTGGATGCGGCCGAGGTCTCCGCCCTCGTCAATGACTGGGCGGGGCTGGGAATGTGGTGGTTCGCC ATAGGCATGATGGCGCTCTGCCTGCTTCTGCTCTGGCTCATCTGCTGCCTCCACCGCAGGCGAGCCAG ACCCCCCATCTATAGACCCATCATTGTCCTGAACCCCGATAATGATGGGATCCATAGATTGGATGGCC TGAAAAACCTACTTTTTTCTTTTACAGTATGATAAATTGAGACATGCCTCGCATTTTCTTGTACATGTT CCTTCTCCCACCTTTTCTGGGGTGTTCTACGCTGGCCGCTGTGTCTCACCTGGAGGTAGACTGCCTCTC ACCCTTCACTGTCTACCTGCTTTACGGATTGGTCACCCTCACTCTCATCTGCAGCCTAATCACAGTAAT CATCGCCTTCATCCAGTGCATTGATTACATCTGTGTGCGCCTCGCATACTTCAGACACCACCCGCAGT ACCGAGACAGGAACATTGCCCAACTTCTAAGACTGCTCTAATCATGCATAAGACTGTGATCTGCCTTC TGATCCTCTGCATCCTGCCCACCCTCACCTCCTGCCAGTACACCACAAAATCTCCGCGCAAAAGACAT GCCTCCTGCCGCTTCACCCAACTGTGGAATATACCCAAATGCTACAACGAAAAGAGCGAGCTCTCCG AAGCTTGGCTGTATGGGGTCATCTGTGTCTTAGTTTTCTGCAGCACTGTCTTTGCCCTCATAATCTACC CCTACTTTGATTTGGGATGGAACGCGATCGATGCCATGAATTACCCCACCTTTCCCGCACCCGAGATA ATTCCACTGCGACAAGTTGTACCCGTTGTCGTTAATCAACGCCCCCCATCCCCTACGCCCACTGAAAT CAGCTACTTTAACCTAACAGGCGGAGATGACTGACGCCCTAGATCTAGAAATGGACGGCATCAGTAC CGAGCAGCGTCTCCTAGAGAGGCGCAGGCAGGCGGCTGAGCAAGAGCGCCTCAATCAGGAGCTCCG AGATCTCGTTAACCTGCACCAGTGCAAAAGAGGCATCTTTTGTCTGGTAAAGCAGGCCAAAGTCACC TACGAGAAGACCGGCAACAGCCACCGCCTCAGTTACAAATTGCCCACCCAGCGCCAGAAGCTGGTGC TCATGGTGGGTGAGAATCCCATCACCGTCACCCAGCACTCGGTAGAGACCGAGGGGTGTCTGCACTC CCCCTGTCGGGGTCCAGAAGACCTCTGCACCCTGGTAAAGACCCTGTGCGGTCTCAGAGATTTAGTC CCCTTTAACTAATCAAACACTGGAATCAATAAAAAGAATCACTTACTTAAAATCAGACAGCAGGTCT CTGTCCAGTTTATTCAGCAGCACCTCCTTCCCCTCCTCCCAACTCTGGTACTCCAAACGCCTTCTGGCG GCAAACTTCCTCCACACCCTGAAGGGAATGTCAGATTCTTGCTCCTGTCCCTCCGCACCCACTATCTT CATGTTGTTGCAGATGAAGCGCACCAAAACGTCTGACGAGAGCTTCAACCCCGTGTACCCCTATGAC ACGGAAAGCGGCCCTCCCTCCGTCCCTTTCCTCACCCCTCCCTTCGTGTCTCCCGATGGATTCCAAGA AAGTCCCCCCGGGGTCCTGTCTCTGAACCTGGCCGAGCCCCTGGTCACTTCCCACGGCATGCTCGCCC TGAAAATGGGAAGTGGCCTCTCCCTGGACGACGCTGGCAACCTCACCTCTCAAGATATCACCACCGC TAGCCCTCCCCTCAAAAAAACCAAGACCAACCTCAGCCTAGAAACCTCATCCCCCCTAACTGTGAGC ACCTCAGGCGCCCTCACCGTAGCAGCCGCCGCTCCCCTGGCGGTGGCCGGCACCTCCCTCACCATGC AATCAGAGGCCCCCCTGACAGTACAGGATGCAAAACTCACCCTGGCCACCAAAGGCCCCCTGACCGT GTCTGAAGGCAAACTGGCCTTGCAAACATCGGCCCCGCTGACGGCCGCTGACAGCAGCACCCTCACA GTCAGTGCCACACCACCCCTTAGCACAAGCAATGGCAGCTTGGGTATTGACATGCAAGCCCCCATTT ACACCACCAATGGAAAACTAGGACTTAACTTTGGCGCTCCCCTGCATGTGGTAGACAGCCTAAATGC ACTGACTGTAGTTACTGGCCAAGGTCTTACGATAAACGGAACAGCCCTACAAACTAGAGTCTCAGGT GCCCTCAACTATGACACATCAGGAAACCTAGAATTGAGAGCTGCAGGGGGTATGCGAGTTGATGCAA ATGGTCAACTTATCCTTGATGTAGCTTACCCATTTGATGCACAAAACAATCTCAGCCTTAGGCTTGGA CAGGGACCCCTGTTTGTTAACTCTGCCCACAACTTGGATGTTAACTACAACAGAGGCCTCTACCTGTT CACATCTGGAAATACCAAAAAGCTAGAAGTTAATATCAAAACAGCCAAGGGTCTCATTTATGATGAC ACTGCTATAGCAATCAATGCGGGTGATGGGCTACAGTTTGACTCAGGCTCAGATACAAATCCATTAA AAACTAAACTTGGATTAGGACTGGATTATGACTCCAGCAGAGCCATAATTGCTAAACTGGGAACTGG CCTAAGCTTTGACAACACAGGTGCCATCACAGTAGGCAACAAAAATGATGACAAGCTTACCTTGTGG ACCACACCAGACCCATCCCCTAACTGTAGAATCTATTCAGAGAAAGATGCTAAATTCACACTTGTTTT GACTAAATGCGGCAGTCAGGTGTTGGCCAGCGTTTCTGTTTTATCTGTAAAAGGTAGCCTTGCGCCCA TCAGTGGCACAGTAACTAGTGCTCAGATTGTCCTCAGATTTGATGAAAATGGAGTTCTACTAAGCAA TTCTTCCCTTGACCCTCAATACTGGAACTACAGAAAAGGTGACCTTACAGAGGGCACTGCATATACC AACGCAGTGGGATTTATGCCCAACCTCACAGCATACCCAAAAACACAGAGCCAAACTGCTAAAAGC AACATTGTAAGTCAGGTTTACTTGAATGGGGACAAATCCAAACCCATGACCCTCACCATTACCCTCA ATGGAACTAATGAAACAGGAGATGCCACAGTAAGCACTTACTCCATGTCATTCTCATGGAACTGGAA TGGAAGTAATTACATTAATGAAACGTTCCAAACCAACTCCTTCACCTTCTCCTACATCGCCCAAGAAT AAAAAGCATGACGCTGTTGATTTGATTCAATGTGTTTCTGTTTTATTTTCAAGCACAACAAAATCATT CAAGTCATTCTTCCATCTTAGCTTAATAGACACAGTAGCTTAATAGACCCAGTAGTGCAAAGCCCCAT TCTAGCTTATAGATCAGACAGTGATAATTAACCACCACCACCACCATACCTTTTGATTCAGGAAATCA TGATCATCACAGGATCCTAGTCTTCAGGCCGCCCCCTCCCTCCCAAGACACAGAATACACAGTCCTCT CCCCCCGACTGGCTTTAAATAACACCATCTGGTTGGTCACAGACATGTTCTTAGGGGTTATATTCCAC ACGGTCTCCTGCCGCGCCAGGCGCTCGTCGGTGATGTTGATAAACTCTCCCGGCAGCTCGCTCAAGTT CACGTCGCTGTCCAGCGGCTGAACCTCCGGCTGACGCGATAACTGTGCGACCGGCTGCTGGACGAAC GGAGGCCGCGCCTACAAGGGGGTAGAGTCATAATCCTCGGTCAGGATAGGGCGGTGATGCAGCAGC AGCGAGCGAAACATCTGCTGCCGCCGCCGCTCCGTCCGGCAGGAAAACAACACGCCGGTGGTCTCCT CCGCGATAATCCGCACCGCCCGCAGCATCAGCTTCCTCGTTCTCCGCGCGCAGCACCTCACCCTTATC TCGCTCAAATCGGCGCAGTAGGTACAGCACAGCACCACGATGTTATTCATGATCCCACAGTGCAGGG CGCTGTATCCAAAGCTCATGCCGGGAACCACCGCCCCCACGTGGCCATCGTACCACAAGCGCACGTA AATCAAGTGTCGACCCCTCATGAACGCGCTGGACACAAACATTACTTCCTTGGGCATGTTGTAATTCA CCACCTCCCGGTACCAGATAAACCTCTGGTTGAACAGGGCACCTTCCACCACCATCCTGAACCAAGA GGCCAGAACCTGCCCACCGGCTATGCACTGCAGGGAACCCGGGTTGGAACAATGACAATGCAGACT CCAAGGCTCGTAACCGTGGATCATCCGGCTGCTGAAGGCATCGATGTTGGCACAACACAGACACACG TGCATGCACTTTCTCATGATTAGCAGCTCTTCCCTCGTCAGGATCATATCCCAAGGAATAACCCATTC TTGAATCAACGTAAAACCCACACAGCAGGGAAGGCCTCGCACATAACTCACGTTGTGCATGGTCAGC GTGTTGCATTCCGGAAACAGCGGATGATCCTCCAGTATCGAGGCGCGGGTCTCCTTCTCACAGGGAG GTAAAGGGTCCCTGCTGTACGGACTGCGCCGGGACGACCGAGATCGTGTTGAGCGTAGTGTCATGGA AAAGGGAACGCCGGACGTGGTCATACTTCTTGAAGCAGAACCAGGTTCGCGCGTGGCAGGCCTCCTT GCGTCTGCGGTCTCGCCGTCTAGCTCGCTCCGTGTGATAGTTGTAGTACAGCCACTCCCGCAGAGCGT CGAGGCGCACCCTGGCTTCCGGATCTATGTAGACTCCGTCTTGCACCGCGGCCCTGATAATATCCACC ACCGTAGAATAAGCAACACCCAGCCAAGCAATACACTCGCTCTGCGAGCGGCAGACAGGAGGAGCG GGCAGAGATGGGAGAACCATGATAAAAAACTTTTTTTAAAGAATATTTTCCAATTCTTCGAAAGTAA GATCTATCAAGTGGCAGCGCTCCCCTCCACTGGCGCGGTCAAACTCTACGGCCAAAGCACAGACAAC GGCATTTCTAAGATGTTCCTTAATGGCGTCCAAAAGACACACCGCTCTCAAGTTGCAGTAAACTATG AATGAAAACCCATCCGGCTGATTTTCCAATATAGACGCGCCGGCAGCGTCCACCAAACCCAGATAAT TTTCTTCTCTCCAGCGGTTTACGATCTGTCTAAGCAAATCCCTTATATCAAGTCCGACCATGCCAAAA ATCTGCTCAAGAGCGCCCTCCACCTTCATGTACAAGCAGCGCATCATGATTGCAAAAATTCAGGTTCT TCAGAGACCTGTATAAGATTCAAAATGGGAACATTAACAAAAATTCCTCTGTCGCGCAGATCCCTTC GCAGGGCAAGCTGAACATAATCAGACAGGTCCGAACGGACCAGTGAGGCCAAATCCCCACCAGGAA CCAGATCCAGAGACCCTATACTGATTATGACGCGCATACTCGGGGCTATGCTGACCAGCGTAGCGCC GATGTAGGCGTGCTGCATGGGCGGCGAGATAAAATGCAAAGTGCTGGTTAAAAAATCAGGCAAAGC CTCGCGCAAAAAAGCTAACACATCATAATCATGCTCATGCAGGTAGTTGCAGGTAAGCTCAGGAACC AAAACGGAATAACACACGATTTTCCTCTCAAACATGACTTCGCGGATACTGCGTAAAACAAAAAATT ATAAATAAAAAATTAATTAAATAACTTAAACATTGGAAGCCTGTCTCACAACAGGAAAAACCACTTT AATCAACATAAGACGGGCCACGGGCATGCCGGCATAGCCGTAAAAAAATTGGTCCCCGTGATTAAC AAGTACCACAGACAGCTCCCCGGTCATGTCGGGGGTCATCATGTGAGACTCTGTATACACGTCTGGA TTGTGAACATCAGACAAACAAAGAAATCGAGCCACGTAGCCCGGAGGTATAATCACCCGCAGGCGG AGGTACAGCAAAACGACCCCCATAGGAGGAATCACAAAATTAGTAGGAGAAAAAAATACATAAACA CCAGAAAAACCCTGTTGCTGAGGCAAAATAGCGCCCTCCCGATCCAAAACAACATAAAGCGCTTCCA CAGGAGCAGCCATAACAAAGACCCGAGTCTTACCAGTAAAAGAAAAAAGATCTCTCAACGCAGCAC CAGCACCAACACTTCGCAGTGTAAAAGGCCAAGTGCCGAGAGAGTATATATAGGAATAAAAAGTGA CGTAAACGGGCAAAGTCCAAAAAACGCCCAGAAAAACCGCACGCGAACCTACGCCCCGAAACGAAA GCCAAAAAACACTAGACACTCCCTTCCGGCGTCAACTTCCGCTTTCCCACGCTACGTCACTTCCCCCG GTCAAACAAACTACATATCCCGAACTTCCAAGTCGCCACGCCCAAAACACCGCCTACACCTCCCCGC CCGCCGGCCCGCCCCCGGACCCGCCTCCCGCCCCGCGCCGCCCATCTCATTATCATATTGGCTTCAAT CCAAAATAAGGTATATTATTGATGATG Polynucleotide sequence encoding ChAd155/RSV SEQ ID NO: 11 CATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAATGAGATGGGCGGCGCGGGGCG GGGCGCGGGGCGGGAGGCGGGTTTGGGGGCGGGCCGGCGGGCGGGGCGGTGTGGCGGAAGTGGAC TTTGTAAGTGTGGCGGATGTGACTTGCTAGTGCCGGGCGCGGTAAAAGTGACGTTTTCCGTGCGCGA CAACGCCCCCGGGAAGTGACATTTTTCCCGCGGTTTTTACCGGATGTTGTAGTGAATTTGGGCGTAAC CAAGTAAGATTTGGCCATTTTCGCGGGAAAACTGAAACGGGGAAGTGAAATCTGATTAATTTTGCGT TAGTCATACCGCGTAATATTTGTCTAGGGCCGAGGGACTTTGGCCGATTACGTGGAGGACTCGCCCA GGTGTTTTTTGAGGTGAATTTCCGCGTTCCGGGTCAAAGTCTGCGTTTTATTATTATAGGATATCCCAT TGCATACGTTGTATCCATATCATAATATGTACATTTATATTGGCTCATGTCCAACATTACCGCCATGTT GACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATG GAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCAT TGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGT GGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCT ATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCC TACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCA ATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAG TTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAA TGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCTCCCTATCAGTGATAGAGATCT CCCTATCAGTGATAGAGATCGTCGACGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCAT CCACGCTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCGCGGCCGGGAACGGTGCA TTGGAACGCGGATTCCCCGTGCCAAGAGTGAGATCTTCCGTTTATCTAGGTACCAGATATCGCCACCA TGGAACTGCTGATCCTGAAGGCCAACGCCATCACCACCATCCTGACCGCCGTGACCTTCTGCTTCGCC AGCGGCCAGAACATCACCGAGGAATTCTACCAGAGCACCTGTAGCGCCGTGAGCAAGGGCTACCTG AGCGCCCTGAGAACCGGCTGGTACACCAGCGTGATCACCATCGAGCTGAGCAACATCAAAGAAAAC AAGTGCAACGGCACCGACGCCAAAGTGAAGCTGATCAAGCAGGAACTGGACAAGTACAAGAACGCC GTGACCGAGCTGCAGCTGCTGATGCAGAGCACCCCCGCCACCAACAACCGGGCCAGACGGGAGCTG CCCCGGTTCATGAACTACACCCTGAACAACGCCAAAAAGACCAACGTGACCCTGAGCAAGAAGCGG AAGCGGCGGTTCCTGGGCTTTCTGCTGGGCGTGGGCAGCGCCATTGCCAGCGGCGTGGCCGTGTCTA AGGTGCTGCACCTGGAAGGCGAAGTGAACAAGATCAAGAGCGCCCTGCTGAGCACCAACAAGGCCG TGGTGTCCCTGAGCAACGGCGTGAGCGTGCTGACCAGCAAGGTGCTGGATCTGAAGAACTACATCGA CAAGCAGCTGCTGCCCATCGTGAACAAGCAGAGCTGCAGCATCAGCAACATCGAGACAGTGATCGA GTTCCAGCAGAAGAACAACCGGCTGCTGGAAATCACCCGGGAGTTCAGCGTGAACGCCGGCGTGAC CACCCCTGTGTCCACCTACATGCTGACCAACAGCGAGCTGCTGAGCCTGATCAACGACATGCCCATC ACCAACGACCAGAAAAAGCTGATGAGCAACAACGTGCAGATCGTGCGGCAGCAGAGCTACTCCATC ATGTCCATCATCAAAGAAGAGGTGCTGGCCTACGTGGTGCAGCTGCCCCTGTACGGCGTGATCGACA CCCCCTGCTGGAAGCTGCACACCAGCCCCCTGTGCACCACCAACACCAAAGAGGGCAGCAACATCTG CCTGACCCGGACCGACAGAGGCTGGTACTGCGACAACGCCGGCAGCGTGTCATTCTTTCCACAGGCC GAGACATGCAAGGTGCAGAGCAACCGGGTGTTCTGCGACACCATGAACAGCCTGACCCTGCCCTCCG AAGTGAACCTGTGCAACGTGGACATCTTCAACCCCAAGTACGACTGCAAGATCATGACCTCCAAGAC CGACGTGTCCAGCTCCGTGATCACCTCCCTGGGCGCCATCGTGTCCTGCTACGGCAAGACCAAGTGC ACCGCCAGCAACAAGAACCGGGGCATCATCAAGACCTTCAGCAACGGCTGCGACTACGTGTCCAAC AAGGGGGTGGACACCGTGTCCGTGGGCAACACCCTGTACTACGTGAACAAACAGGAAGGCAAGAGC CTGTACGTGAAGGGCGAGCCCATCATCAACTTCTACGACCCCCTGGTGTTCCCCAGCGACGAGTTCG ACGCCAGCATCAGCCAGGTGAACGAGAAGATCAACCAGAGCCTGGCCTTCATCCGGAAGTCCGACG AGCTGCTGCACAATGTGAATGCCGGCAAGTCCACCACCAACCGGAAGCGGAGAGCCCCTGTGAAGC AGACCCTGAACTTCGACCTGCTGAAGCTGGCCGGCGACGTGGAGAGCAATCCCGGCCCTATGGCCCT GAGCAAAGTGAAACTGAACGATACACTGAACAAGGACCAGCTGCTGTCCAGCAGCAAGTACACCAT CCAGCGGAGCACCGGCGACAGCATCGATACCCCCAACTACGACGTGCAGAAGCACATCAACAAGCT GTGCGGCATGCTGCTGATCACAGAGGACGCCAACCACAAGTTCACCGGCCTGATCGGCATGCTGTAC GCCATGAGCCGGCTGGGCCGGGAGGACACCATCAAGATCCTGCGGGACGCCGGCTACCACGTGAAG GCCAATGGCGTGGACGTGACCACACACCGGCAGGACATCAACGGCAAAGAAATGAAGTTCGAGGTG CTGACCCTGGCCAGCCTGACCACCGAGATCCAGATCAATATCGAGATCGAGAGCCGGAAGTCCTACA AGAAAATGCTGAAAGAAATGGGCGAGGTGGCCCCCGAGTACAGACACGACAGCCCCGACTGCGGCA TGATCATCCTGTGTATCGCCGCCCTGGTGATCACAAAGCTGGCCGCTGGCGACAGATCTGGCCTGAC AGCCGTGATCAGACGGGCCAACAATGTGCTGAAGAACGAGATGAAGCGGTACAAGGGCCTGCTGCC CAAGGACATTGCCAACAGCTTCTACGAGGTGTTCGAGAAGTACCCCCACTTCATCGACGTGTTCGTG CACTTCGGCATTGCCCAGAGCAGCACCAGAGGCGGCTCCAGAGTGGAGGGCATCTTCGCCGGCCTGT TCATGAACGCCTACGGCGCTGGCCAGGTGATGCTGAGATGGGGCGTGCTGGCCAAGAGCGTGAAGA ACATCATGCTGGGCCACGCCAGCGTGCAGGCCGAGATGGAACAGGTGGTGGAGGTGTACGAGTACG CCCAGAAGCTGGGCGGAGAGGCCGGCTTCTACCACATCCTGAACAACCCTAAGGCCTCCCTGCTGTC CCTGACCCAGTTCCCCCACTTCTCCAGCGTGGTGCTGGGAAATGCCGCCGGACTGGGCATCATGGGC GAGTACCGGGGCACCCCCAGAAACCAGGACCTGTACGACGCCGCCAAGGCCTACGCCGAGCAGCTG AAAGAAAACGGCGTGATCAACTACAGCGTGCTGGACCTGACCGCTGAGGAACTGGAAGCCATCAAG CACCAGCTGAACCCCAAGGACAACGACGTGGAGCTGGGAGGCGGAGGATCTGGCGGCGGAGGCATG AGCAGACGGAACCCCTGCAAGTTCGAGATCCGGGGCCACTGCCTGAACGGCAAGCGGTGCCACTTCA GCCACAACTACTTCGAGTGGCCCCCTCATGCTCTGCTGGTGCGGCAGAACTTCATGCTGAACCGGATC CTGAAGTCCATGGACAAGAGCATCGACACCCTGAGCGAGATCAGCGGAGCCGCCGAGCTGGACAGA ACCGAGGAATATGCCCTGGGCGTGGTGGGAGTGCTGGAAAGCTACATCGGCTCCATCAACAACATCA CAAAGCAGAGCGCCTGCGTGGCCATGAGCAAGCTGCTGACAGAGCTGAACAGCGACGACATCAAGA AGCTGAGGGACAACGAGGAACTGAACAGCCCCAAGATCCGGGTGTACAACACCGTGATCAGCTACA TTGAGAGCAACCGCAAGAACAACAAGCAGACCATCCATCTGCTGAAGCGGCTGCCCGCCGACGTGCT GAAAAAGACCATCAAGAACACCCTGGACATCCACAAGTCCATCACCATCAACAATCCCAAAGAAAG CACCGTGTCTGACACCAACGATCACGCCAAGAACAACGACACCACCTGATGAGCGGCCGCGATCTGC TGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGC CACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTA TTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTG GGGATGCGGTGGGCTCTATGGCCGATCAGCGATCGCTGAGGTGGGTGAGTGGGCGTGGCCTGGGGTG GTCATGAAAATATATAAGTTGGGGGTCTTAGGGTCTCTTTATTTGTGTTGCAGAGACCGCCGGAGCCA TGAGCGGGAGCAGCAGCAGCAGCAGTAGCAGCAGCGCCTTGGATGGCAGCATCGTGAGCCCTTATTT GACGACGCGGATGCCCCACTGGGCCGGGGTGCGTCAGAATGTGATGGGCTCCAGCATCGACGGCCG ACCCGTCCTGCCCGCAAATTCCGCCACGCTGACCTATGCGACCGTCGCGGGGACGCCGTTGGACGCC ACCGCCGCCGCCGCCGCCACCGCAGCCGCCTCGGCCGTGCGCAGCCTGGCCACGGACTTTGCATTCC TGGGACCACTGGCGACAGGGGCTACTTCTCGGGCCGCTGCTGCCGCCGTTCGCGATGACAAGCTGAC CGCCCTGCTGGCGCAGTTGGATGCGCTTACTCGGGAACTGGGTGACCTTTCTCAGCAGGTCATGGCCC TGCGCCAGCAGGTCTCCTCCCTGCAAGCTGGCGGGAATGCTTCTCCCACAAATGCCGTTTAAGATAA ATAAAACCAGACTCTGTTTGGATTAAAGAAAAGTAGCAAGTGCATTGCTCTCTTTATTTCATAATTTT CCGCGCGCGATAGGCCCTAGACCAGCGTTCTCGGTCGTTGAGGGTGCGGTGTATCTTCTCCAGGACG TGGTAGAGGTGGCTCTGGACGTTGAGATACATGGGCATGAGCCCGTCCCGGGGGTGGAGGTAGCACC ACTGCAGAGCTTCATGCTCCGGGGTGGTGTTGTAGATGATCCAGTCGTAGCAGGAGCGCTGGGCATG GTGCCTAAAAATGTCCTTCAGCAGCAGGCCGATGGCCAGGGGGAGGCCCTTGGTGTAAGTGTTTACA AAACGGTTAAGTTGGGAAGGGTGCATTCGGGGAGAGATGATGTGCATCTTGGACTGTATTTTTAGAT TGGCGATGTTTCCGCCCAGATCCCTTCTGGGATTCATGTTGTGCAGGACCACCAGTACAGTGTATCCG GTGCACTTGGGGAATTTGTCATGCAGCTTAGAGGGAAAAGCGTGGAAGAACTTGGAGACGCCTTTGT GGCCTCCCAGATTTTCCATGCATTCGTCCATGATGATGGCAATGGGCCCGCGGGAGGCAGCTTGGGC AAAGATATTTCTGGGGTCGCTGACGTCGTAGTTGTGTTCCAGGGTGAGGTCGTCATAGGCCATTTTTA CAAAGCGCGGGCGGAGGGTGCCCGACTGGGGGATGATGGTCCCCTCTGGCCCTGGGGCGTAGTTGCC CTCGCAGATCTGCATTTCCCAGGCCTTAATCTCGGAGGGGGGAATCATATCCACCTGCGGGGCGATG AAGAAAACGGTTTCCGGAGCCGGGGAGATTAACTGGGATGAGAGCAGGTTTCTAAGCAGCTGTGATT TTCCACAACCGGTGGGCCCATAAATAACACCTATAACCGGTTGCAGCTGGTAGTTTAGAGAGCTGCA GCTGCCGTCGTCCCGGAGGAGGGGGGCCACCTCGTTGAGCATGTCCCTGACGCGCATGTTCTCCCCG ACCAGATCCGCCAGAAGGCGCTCGCCGCCCAGGGACAGCAGCTCTTGCAAGGAAGCAAAGTTTTTCA GCGGCTTGAGGCCGTCCGCCGTGGGCATGTTTTTCAGGGTCTGGCTCAGCAGCTCCAGGCGGTCCCA GAGCTCGGTGACGTGCTCTACGGCATCTCTATCCAGCATATCTCCTCGTTTCGCGGGTTGGGGCGACT TTCGCTGTAGGGCACCAAGCGGTGGTCGTCCAGCGGGGCCAGAGTCATGTCCTTCCATGGGCGCAGG GTCCTCGTCAGGGTGGTCTGGGTCACGGTGAAGGGGTGCGCTCCGGGCTGAGCGCTTGCCAAGGTGC GCTTGAGGCTGGTTCTGCTGGTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGCGTCGGCCAGGTAGCAT TTGACCATGGTGTCATAGTCCAGCCCCTCCGCGGCGTGTCCCTTGGCGCGCAGCTTGCCCTTGGAGGT GGCGCCGCACGAGGGGCAGAGCAGGCTCTTGAGCGCGTAGAGCTTGGGGGCGAGGAAGACCGATTC GGGGGAGTAGGCGTCCGCGCCGCAGACCCCGCACACGGTCTCGCACTCCACCAGCCAGGTGAGCTCG GGGCGCGCCGGGTCAAAAACCAGGTTTCCCCCATGCTTTTTGATGCGTTTCTTACCTCGGGTCTCCAT GAGGTGGTGTCCCCGCTCGGTGACGAAGAGGCTGTCCGTGTCTCCGTAGACCGACTTGAGGGGTCTT TTCTCCAGGGGGGTCCCTCGGTCTTCCTCGTAGAGGAACTCGGACCACTCTGAGACGAAGGCCCGCG TCCAGGCCAGGACGAAGGAGGCTATGTGGGAGGGGTAGCGGTCGTTGTCCACTAGGGGGTCCACCTT CTCCAAGGTGTGAAGACACATGTCGCCTTCCTCGGCGTCCAGGAAGGTGATTGGCTTGTAGGTGTAG GCCACGTGACCGGGGGTTCCTGACGGGGGGGTATAAAAGGGGGTGGGGGCGCGCTCGTCGTCACTCT CTTCCGCATCGCTGTCTGCGAGGGCCAGCTGCTGGGGTGAGTATTCCCTCTCGAAGGCGGGCATGAC CTCCGCGCTGAGGTTGTCAGTTTCCAAAAACGAGGAGGATTTGATGTTCACCTGTCCCGAGGTGATA CCTTTGAGGGTACCCGCGTCCATCTGGTCAGAAAACACGATCTTTTTATTGTCCAGCTTGGTGGCGAA CGACCCGTAGAGGGCGTTGGAGAGCAGCTTGGCGATGGAGCGCAGGGTCTGGTTCTTGTCCCTGTCG GCGCGCTCCTTGGCCGCGATGTTGAGCTGCACGTACTCGCGCGCGACGCAGCGCCACTCGGGGAAGA CGGTGGTGCGCTCGTCGGGCACCAGGCGCACGCGCCAGCCGCGGTTGTGCAGGGTGACCAGGTCCAC GCTGGTGGCGACCTCGCCGCGCAGGCGCTCGTTGGTCCAGCAGAGACGGCCGCCCTTGCGCGAGCAG AAGGGGGGCAGGGGGTCGAGCTGGGTCTCGTCCGGGGGGTCCGCGTCCACGGTGAAAACCCCGGGG CGCAGGCGCGCGTCGAAGTAGTCTATCTTGCAACCTTGCATGTCCAGCGCCTGCTGCCAGTCGCGGG CGGCGAGCGCGCGCTCGTAGGGGTTGAGCGGCGGGCCCCAGGGCATGGGGTGGGTGAGTGCGGAGG CGTACATGCCGCAGATGTCATAGACGTAGAGGGGCTCCCGCAGGACCCCGATGTAGGTGGGGTAGC AGCGGCCGCCGCGGATGCTGGCGCGCACGTAGTCATACAGCTCGTGCGAGGGGGCGAGGAGGTCGG GGCCCAGGTTGGTGCGGGCGGGGCGCTCCGCGCGGAAGACGATCTGCCTGAAGATGGCATGCGAGT TGGAAGAGATGGTGGGGCGCTGGAAGACGTTGAAGCTGGCGTCCTGCAGGCCGACGGCGTCGCGCA CGAAGGAGGCGTAGGAGTCGCGCAGCTTGTGTACCAGCTCGGCGGTGACCTGCACGTCGAGCGCGC AGTAGTCGAGGGTCTCGCGGATGATGTCATATTTAGCCTGCCCCTTCTTTTTCCACAGCTCGCGGTTG AGGACAAACTCTTCGCGGTCTTTCCAGTACTCTTGGATCGGGAAACCGTCCGGTTCCGAACGGTAAG AGCCTAGCATGTAGAACTGGTTGACGGCCTGGTAGGCGCAGCAGCCCTTCTCCACGGGGAGGGCGTA GGCCTGCGCGGCCTTGCGGAGCGAGGTGTGGGTCAGGGCGAAGGTGTCCCTGACCATGACTTTGAGG TACTGGTGCTTGAAGTCGGAGTCGTCGCAGCCGCCCCGCTCCCAGAGCGAGAAGTCGGTGCGCTTCT TGGAGCGGGGGTTGGGCAGAGCGAAGGTGACATCGTTGAAGAGGATTTTGCCCGCGCGGGGCATGA AGTTGCGGGTGATGCGGAAGGGCCCCGGCACTTCAGAGCGGTTGTTGATGACCTGGGCGGCGAGCAC GATCTCGTCGAAGCCGTTGATGTTGTGGCCCACGATGTAGAGTTCCAGGAAGCGGGGCCGGCCCTTT ACGGTGGGCAGCTTCTTTAGCTCTTCGTAGGTGAGCTCCTCGGGCGAGGCGAGGCCGTGCTCGGCCA GGGCCCAGTCCGCGAGGTGCGGGTTGTCTCTGAGGAAGGACTTCCAGAGGTCGCGGGCCAGGAGGG TCTGCAGGCGGTCTCTGAAGGTCCTGAACTGGCGGCCCACGGCCATTTTTTCGGGGGTGATGCAGTA GAAGGTGAGGGGGTCTTGCTGCCAGCGGTCCCAGTCGAGCTGCAGGGCGAGGTCGCGCGCGGCGGT GACCAGGCGCTCGTCGCCCCCGAATTTCATGACCAGCATGAAGGGCACGAGCTGCTTTCCGAAGGCC CCCATCCAAGTGTAGGTCTCTACATCGTAGGTGACAAAGAGGCGCTCCGTGCGAGGATGCGAGCCGA TCGGGAAGAACTGGATCTCCCGCCACCAGTTGGAGGAGTGGCTGTTGATGTGGTGGAAGTAGAAGTC CCGTCGCCGGGCCGAACACTCGTGCTGGCTTTTGTAAAAGCGAGCGCAGTACTGGCAGCGCTGCACG GGCTGTACCTCATGCACGAGATGCACCTTTCGCCCGCGCACGAGGAAGCCGAGGGGAAATCTGAGCC CCCCGCCTGGCTCGCGGCATGGCTGGTTCTCTTCTACTTTGGATGCGTGTCCGTCTCCGTCTGGCTCCT CGAGGGGTGTTACGGTGGAGCGGACCACCACGCCGCGCGAGCCGCAGGTCCAGATATCGGCGCGCG GCGGTCGGAGTTTGATGACGACATCGCGCAGCTGGGAGCTGTCCATGGTCTGGAGCTCCCGCGGCGG CGGCAGGTCAGCCGGGAGTTCTTGCAGGTTCACCTCGCAGAGTCGGGCCAGGGCGCGGGGCAGGTCT AGGTGGTACCTGATCTCTAGGGGCGTGTTGGTGGCGGCGTCGATGGCTTGCAGGAGCCCGCAGCCCC GGGGGGCGACGACGGTGCCCCGCGGGGTGGTGGTGGTGGTGGCGGTGCAGCTCAGAAGCGGTGCCG CGGGCGGGCCCCCGGAGGTAGGGGGGGCTCCGGTCCCGCGGGCAGGGGCGGCAGCGGCACGTCGGC GTGGAGCGCGGGCAGGAGTTGGTGCTGTGCCCGGAGGTTGCTGGCGAAGGCGACGACGCGGCGGTT GATCTCCTGGATCTGGCGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCTTGAACCTGAAAGAGAGT TCGACAGAATCAATCTCGGTGTCATTGACCGCGGCCTGGCGCAGGATCTCCTGCACGTCTCCCGAGTT GTCTTGGTAGGCGATCTCGGCCATGAACTGCTCGATCTCTTCCTCCTGGAGGTCTCCGCGTCCGGCGC GTTCCACGGTGGCCGCCAGGTCGTTGGAGATGCGCCCCATGAGCTGCGAGAAGGCGTTGAGTCCGCC CTCGTTCCAGACTCGGCTGTAGACCACGCCCCCCTGGTCATCGCGGGCGCGCATGACCACCTGCGCG AGGTTGAGCTCCACGTGCCGCGCGAAGACGGCGTAGTTGCGCAGACGCTGGAAGAGGTAGTTGAGG GTGGTGGCGGTGTGCTCGGCCACGAAGAAGTTCATGACCCAGCGGCGCAACGTGGATTCGTTGATGT CCCCCAAGGCCTCCAGCCGTTCCATGGCCTCGTAGAAGTCCACGGCGAAGTTGAAAAACTGGGAGTT GCGCGCCGACACGGTCAACTCCTCCTCCAGAAGACGGATGAGCTCGGCGACGGTGTCGCGCACCTCG CGCTCGAAGGCTATGGGGATCTCTTCCTCCGCTAGCATCACCACCTCCTCCTCTTCCTCCTCTTCTGGC ACTTCCATGATGGCTTCCTCCTCTTCGGGGGGTGGCGGCGGCGGCGGTGGGGGAGGGGGCGCTCTGC GCCGGCGGCGGCGCACCGGGAGGCGGTCCACGAAGCGCGCGATCATCTCCCCGCGGCGGCGGCGCA TGGTCTCGGTGACGGCGCGGCCGTTCTCCCGGGGGCGCAGTTGGAAGACGCCGCCGGACATCTGGTG CTGGGGCGGGTGGCCGTGAGGCAGCGAGACGGCGCTGACGATGCATCTCAACAATTGCTGCGTAGGT ACGCCGCCGAGGGACCTGAGGGAGTCCATATCCACCGGATCCGAAAACCTTTCGAGGAAGGCGTCTA ACCAGTCGCAGTCGCAAGGTAGGCTGAGCACCGTGGCGGGCGGCGGGGGGTGGGGGGAGTGTCTGG CGGAGGTGCTGCTGATGATGTAATTGAAGTAGGCGGACTTGACACGGCGGATGGTCGACAGGAGCA CCATGTCCTTGGGTCCGGCCTGCTGGATGCGGAGGCGGTCGGCTATGCCCCAGGCTTCGTTCTGGCAT CGGCGCAGGTCCTTGTAGTAGTCTTGCATGAGCCTTTCCACCGGCACCTCTTCTCCTTCCTCTTCTGCT TCTTCCATGTCTGCTTCGGCCCTGGGGCGGCGCCGCGCCCCCCTGCCCCCCATGCGCGTGACCCCGAA CCCCCTGAGCGGTTGGAGCAGGGCCAGGTCGGCGACGACGCGCTCGGCCAGGATGGCCTGCTGCACC TGCGTGAGGGTGGTTTGGAAGTCATCCAAGTCCACGAAGCGGTGGTAGGCGCCCGTGTTGATGGTGT AGGTGCAGTTGGCCATGACGGACCAGTTGACGGTCTGGTGGCCCGGTTGCGACATCTCGGTGTACCT GAGTCGCGAGTAGGCGCGGGAGTCGAAGACGTAGTCGTTGCAAGTCCGCACCAGGTACTGGTAGCC CACCAGGAAGTGCGGCGGCGGCTGGCGGTAGAGGGGCCAGCGCAGGGTGGCGGGGGCTCCGGGGGC CAGGTCTTCCAGCATGAGGCGGTGGTAGGCGTAGATGTACCTGGACATCCAGGTGATACCCGCGGCG GTGGTGGAGGCGCGCGGGAAGTCGCGCACCCGGTTCCAGATGTTGCGCAGGGGCAGAAAGTGCTCC ATGGTAGGCGTGCTCTGTCCAGTCAGACGCGCGCAGTCGTTGATACTCTAGACCAGGGAAAACGAAA GCCGGTCAGCGGGCACTCTTCCGTGGTCTGGTGAATAGATCGCAAGGGTATCATGGCGGAGGGCCTC GGTTCGAGCCCCGGGTCCGGGCCGGACGGTCCGCCATGATCCACGCGGTTACCGCCCGCGTGTCGAA CCCAGGTGTGCGACGTCAGACAACGGTGGAGTGTTCCTTTTGGCGTTTTTCTGGCCGGGCGCCGGCGC CGCGTAAGAGACTAAGCCGCGAAAGCGAAAGCAGTAAGTGGCTCGCTCCCCGTAGCCGGAGGGATC CTTGCTAAGGGTTGCGTTGCGGCGAACCCCGGTTCGAATCCCGTACTCGGGCCGGCCGGACCCGCGG CTAAGGTGTTGGATTGGCCTCCCCCTCGTATAAAGACCCCGCTTGCGGATTGACTCCGGACACGGGG ACGAGCCCCTTTTATTTTTGCTTTCCCCAGATGCATCCGGTGCTGCGGCAGATGCGCCCCCCGCCCCA GCAGCAGCAACAACACCAGCAAGAGCGGCAGCAACAGCAGCGGGAGTCATGCAGGGCCCCCTCACC CACCCTCGGCGGGCCGGCCACCTCGGCGTCCGCGGCCGTGTCTGGCGCCTGCGGCGGCGGCGGGGGG CCGGCTGACGACCCCGAGGAGCCCCCGCGGCGCAGGGCCAGACACTACCTGGACCTGGAGGAGGGC GAGGGCCTGGCGCGGCTGGGGGCGCCGTCTCCCGAGCGCCACCCGCGGGTGCAGCTGAAGCGCGAC TCGCGCGAGGCGTACGTGCCTCGGCAGAACCTGTTCAGGGACCGCGCGGGCGAGGAGCCCGAGGAG ATGCGGGACAGGAGGTTCAGCGCAGGGCGGGAGCTGCGGCAGGGGCTGAACCGCGAGCGGCTGCTG CGCGAGGAGGACTTTGAGCCCGACGCGCGGACGGGGATCAGCCCCGCGCGCGCGCACGTGGCGGCC GCCGACCTGGTGACGGCGTACGAGCAGACGGTGAACCAGGAGATCAACTTCCAAAAGAGTTTCAAC AACCACGTGCGCACGCTGGTGGCGCGCGAGGAGGTGACCATCGGGCTGATGCACCTGTGGGACTTTG TAAGCGCGCTGGTGCAGAACCCCAACAGCAAGCCTCTGACGGCGCAGCTGTTCCTGATAGTGCAGCA CAGCAGGGACAACGAGGCGTTTAGGGACGCGCTGCTGAACATCACCGAGCCCGAGGGTCGGTGGCT GCTGGACCTGATTAACATCCTGCAGAGCATAGTGGTGCAGGAGCGCAGCCTGAGCCTGGCCGACAAG GTGGCGGCCATCAACTACTCGATGCTGAGCCTGGGCAAGTTTTACGCGCGCAAGATCTACCAGACGC CGTACGTGCCCATAGACAAGGAGGTGAAGATCGACGGTTTTTACATGCGCATGGCGCTGAAGGTGCT CACCCTGAGCGACGACCTGGGCGTGTACCGCAACGAGCGCATCCACAAGGCCGTGAGCGTGAGCCG GCGGCGCGAGCTGAGCGACCGCGAGCTGATGCACAGCCTGCAGCGGGCGCTGGCGGGCGCCGGCAG CGGCGACAGGGAGGCGGAGTCCTACTTCGATGCGGGGGCGGACCTGCGCTGGGCGCCCAGCCGGCG GGCCCTGGAGGCCGCGGGGGTCCGCGAGGACTATGACGAGGACGGCGAGGAGGATGAGGAGTACG AGCTAGAGGAGGGCGAGTACCTGGACTAAACCGCGGGTGGTGTTTCCGGTAGATGCAAGACCCGAA CGTGGTGGACCCGGCGCTGCGGGCGGCTCTGCAGAGCCAGCCGTCCGGCCTTAACTCCTCAGACGAC TGGCGACAGGTCATGGACCGCATCATGTCGCTGACGGCGCGTAACCCGGACGCGTTCCGGCAGCAGC CGCAGGCCAACAGGCTCTCCGCCATCCTGGAGGCGGTGGTGCCTGCGCGCTCGAACCCCACGCACGA GAAGGTGCTGGCCATAGTGAACGCGCTGGCCGAGAACAGGGCCATCCGCCCGGACGAGGCCGGGCT GGTGTACGACGCGCTGCTGCAGCGCGTGGCCCGCTACAACAGCGGCAACGTGCAGACCAACCTGGA CCGGCTGGTGGGGGACGTGCGCGAGGCGGTGGCGCAGCGCGAGCGCGCGGATCGGCAGGGCAACCT GGGCTCCATGGTGGCGCTGAATGCCTTCCTGAGCACGCAGCCGGCCAACGTGCCGCGGGGGCAGGA AGACTACACCAACTTTGTGAGCGCGCTGCGGCTGATGGTGACCGAGACCCCCCAGAGCGAGGTGTAC CAGTCGGGCCCGGACTACTTCTTCCAGACCAGCAGACAGGGCCTGCAGACGGTGAACCTGAGCCAGG CTTTCAAGAACCTGCGGGGGCTGTGGGGCGTGAAGGCGCCCACCGGCGACCGGGCGACGGTGTCCA GCCTGCTGACGCCCAACTCGCGCCTGCTGCTGCTGCTGATCGCGCCGTTCACGGACAGCGGCAGCGT GTCCCGGGACACCTACCTGGGGCACCTGCTGACCCTGTACCGCGAGGCCATCGGGCAGGCGCAGGTG GACGAGCACACCTTCCAGGAGATCACCAGCGTGAGCCGCGCGCTGGGGCAGGAGGACACGAGCAGC CTGGAGGCGACTCTGAACTACCTGCTGACCAACCGGCGGCAGAAGATTCCCTCGCTGCACAGCCTGA CCTCCGAGGAGGAGCGCATCTTGCGCTACGTGCAGCAGAGCGTGAGCCTGAACCTGATGCGCGACGG GGTGACGCCCAGCGTGGCGCTGGACATGACCGCGCGCAACATGGAACCGGGCATGTACGCCGCGCA CCGGCCTTACATCAACCGCCTGATGGACTACCTGCATCGCGCGGCGGCCGTGAACCCCGAGTACTTT ACCAACGCCATCCTGAACCCGCACTGGCTCCCGCCGCCCGGGTTCTACAGCGGGGGCTTCGAGGTCC CGGAGACCAACGATGGCTTCCTGTGGGACGACATGGACGACAGCGTGTTCTCCCCGCGGCCGCAGGC GCTGGCGGAAGCGTCCCTGCTGCGTCCCAAGAAGGAGGAGGAGGAGGAGGCGAGTCGCCGCCGCGG CAGCAGCGGCGTGGCTTCTCTGTCCGAGCTGGGGGCGGCAGCCGCCGCGCGCCCCGGGTCCCTGGGC GGCAGCCCCTTTCCGAGCCTGGTGGGGTCTCTGCACAGCGAGCGCACCACCCGCCCTCGGCTGCTGG GCGAGGACGAGTACCTGAATAACTCCCTGCTGCAGCCGGTGCGGGAGAAAAACCTGCCTCCCGCCTT CCCCAACAACGGGATAGAGAGCCTGGTGGACAAGATGAGCAGATGGAAGACCTATGCGCAGGAGCA CAGGGACGCGCCTGCGCTCCGGCCGCCCACGCGGCGCCAGCGCCACGACCGGCAGCGGGGGCTGGT GTGGGATGACGAGGACTCCGCGGACGATAGCAGCGTGCTGGACCTGGGAGGGAGCGGCAACCCGTT CGCGCACCTGCGCCCCCGCCTGGGGAGGATGTTTTAAAAAAAAAAAAAAAAAGCAAGAAGCATGAT GCAAAAATTAAATAAAACTCACCAAGGCCATGGCGACCGAGCGTTGGTTTCTTGTGTTCCCTTCAGT ATGCGGCGCGCGGCGATGTACCAGGAGGGACCTCCTCCCTCTTACGAGAGCGTGGTGGGCGCGGCGG CGGCGGCGCCCTCTTCTCCCTTTGCGTCGCAGCTGCTGGAGCCGCCGTACGTGCCTCCGCGCTACCTG CGGCCTACGGGGGGGAGAAACAGCATCCGTTACTCGGAGCTGGCGCCCCTGTTCGACACCACCCGGG TGTACCTGGTGGACAACAAGTCGGCGGACGTGGCCTCCCTGAACTACCAGAACGACCACAGCAATTT TTTGACCACGGTCATCCAGAACAATGACTACAGCCCGAGCGAGGCCAGCACCCAGACCATCAATCTG GATGACCGGTCGCACTGGGGCGGCGACCTGAAAACCATCCTGCACACCAACATGCCCAACGTGAAC GAGTTCATGTTCACCAATAAGTTCAAGGCGCGGGTGATGGTGTCGCGCTCGCACACCAAGGAAGACC GGGTGGAGCTGAAGTACGAGTGGGTGGAGTTCGAGCTGCCAGAGGGCAACTACTCCGAGACCATGA CCATTGACCTGATGAACAACGCGATCGTGGAGCACTATCTGAAAGTGGGCAGGCAGAACGGGGTCCT GGAGAGCGACATCGGGGTCAAGTTCGACACCAGGAACTTCCGCCTGGGGCTGGACCCCGTGACCGG GCTGGTTATGCCCGGGGTGTACACCAACGAGGCCTTCCATCCCGACATCATCCTGCTGCCCGGCTGCG GGGTGGACTTCACTTACAGCCGCCTGAGCAACCTCCTGGGCATCCGCAAGCGGCAGCCCTTCCAGGA GGGCTTCAGGATCACCTACGAGGACCTGGAGGGGGGCAACATCCCCGCGCTCCTCGATGTGGAGGCC TACCAGGATAGCTTGAAGGAAAATGAGGCGGGACAGGAGGATACCGCCCCCGCCGCCTCCGCCGCC GCCGAGCAGGGCGAGGATGCTGCTGACACCGCGGCCGCGGACGGGGCAGAGGCCGACCCCGCTATG GTGGTGGAGGCTCCCGAGCAGGAGGAGGACATGAATGACAGTGCGGTGCGCGGAGACACCTTCGTC ACCCGGGGGGAGGAAAAGCAAGCGGAGGCCGAGGCCGCGGCCGAGGAAAAGCAACTGGCGGCAGC AGCGGCGGCGGCGGCGTTGGCCGCGGCGGAGGCTGAGTCTGAGGGGACCAAGCCCGCCAAGGAGCC CGTGATTAAGCCCCTGACCGAAGATAGCAAGAAGCGCAGTTACAACCTGCTCAAGGACAGCACCAA CACCGCGTACCGCAGCTGGTACCTGGCCTACAACTACGGCGACCCGTCGACGGGGGTGCGCTCCTGG ACCCTGCTGTGCACGCCGGACGTGACCTGCGGCTCGGAGCAGGTGTACTGGTCGCTGCCCGACATGA TGCAAGACCCCGTGACCTTCCGCTCCACGCGGCAGGTCAGCAACTTCCCGGTGGTGGGCGCCGAGCT GCTGCCCGTGCACTCCAAGAGCTTCTACAACGACCAGGCCGTCTACTCCCAGCTCATCCGCCAGTTCA CCTCTCTGACCCACGTGTTCAATCGCTTTCCTGAGAACCAGATTCTGGCGCGCCCGCCCGCCCCCACC ATCACCACCGTCAGTGAAAACGTTCCTGCTCTCACAGATCACGGGACGCTACCGCTGCGCAACAGCA TCGGAGGAGTCCAGCGAGTGACCGTTACTGACGCCAGACGCCGCACCTGCCCCTACGTTTACAAGGC CTTGGGCATAGTCTCGCCGCGCGTCCTTTCCAGCCGCACTTTTTGAGCAACACCACCATCATGTCCAT CCTGATCTCACCCAGCAATAACTCCGGCTGGGGACTGCTGCGCGCGCCCAGCAAGATGTTCGGAGGG GCGAGGAAGCGTTCCGAGCAGCACCCCGTGCGCGTGCGCGGGCACTTCCGCGCCCCCTGGGGAGCGC ACAAACGCGGCCGCGCGGGGCGCACCACCGTGGACGACGCCATCGACTCGGTGGTGGAGCAGGCGC GCAACTACAGGCCCGCGGTCTCTACCGTGGACGCGGCCATCCAGACCGTGGTGCGGGGCGCGCGGCG GTACGCCAAGCTGAAGAGCCGCCGGAAGCGCGTGGCCCGCCGCCACCGCCGCCGACCCGGGGCCGC CGCCAAACGCGCCGCCGCGGCCCTGCTTCGCCGGGCCAAGCGCACGGGCCGCCGCGCCGCCATGAG GGCCGCGCGCCGCTTGGCCGCCGGCATCACCGCCGCCACCATGGCCCCCCGTACCCGAAGACGCGCG GCCGCCGCCGCCGCCGCCGCCATCAGTGACATGGCCAGCAGGCGCCGGGGCAACGTGTACTGGGTGC GCGACTCGGTGACCGGCACGCGCGTGCCCGTGCGCTTCCGCCCCCCGCGGACTTGAGATGATGTGAA AAAACAACACTGAGTCTCCTGCTGTTGTGTGTATCCCAGCGGCGGCGGCGCGCGCAGCGTCATGTCC AAGCGCAAAATCAAAGAAGAGATGCTCCAGGTCGTCGCGCCGGAGATCTATGGGCCCCCGAAGAAG GAAGAGCAGGATTCGAAGCCCCGCAAGATAAAGCGGGTCAAAAAGAAAAAGAAAGATGATGACGA TGCCGATGGGGAGGTGGAGTTCCTGCGCGCCACGGCGCCCAGGCGCCCGGTGCAGTGGAAGGGCCG GCGCGTAAAGCGCGTCCTGCGCCCCGGCACCGCGGTGGTCTTCACGCCCGGCGAGCGCTCCACCCGG ACTTTCAAGCGCGTCTATGACGAGGTGTACGGCGACGAAGACCTGCTGGAGCAGGCCAACGAGCGCT TCGGAGAGTTTGCTTACGGGAAGCGTCAGCGGGCGCTGGGGAAGGAGGACCTGCTGGCGCTGCCGCT GGACCAGGGCAACCCCACCCCCAGTCTGAAGCCCGTGACCCTGCAGCAGGTGCTGCCGAGCAGCGC ACCCTCCGAGGCGAAGCGGGGTCTGAAGCGCGAGGGCGGCGACCTGGCGCCCACCGTGCAGCTCAT GGTGCCCAAGCGGCAGAGGCTGGAGGATGTGCTGGAGAAAATGAAAGTAGACCCCGGTCTGCAGCC GGACATCAGGGTCCGCCCCATCAAGCAGGTGGCGCCGGGCCTCGGCGTGCAGACCGTGGACGTGGTC ATCCCCACCGGCAACTCCCCCGCCGCCGCCACCACTACCGCTGCCTCCACGGACATGGAGACACAGA CCGATCCCGCCGCAGCCGCAGCCGCAGCCGCCGCCGCGACCTCCTCGGCGGAGGTGCAGACGGACCC CTGGCTGCCGCCGGCGATGTCAGCTCCCCGCGCGCGTCGCGGGCGCAGGAAGTACGGCGCCGCCAAC GCGCTCCTGCCCGAGTACGCCTTGCATCCTTCCATCGCGCCCACCCCCGGCTACCGAGGCTATACCTA CCGCCCGCGAAGAGCCAAGGGTTCCACCCGCCGTCCCCGCCGACGCGCCGCCGCCACCACCCGCCGC CGCCGCCGCAGACGCCAGCCCGCACTGGCTCCAGTCTCCGTGAGGAAAGTGGCGCGCGACGGACAC ACCCTGGTGCTGCCCAGGGCGCGCTACCACCCCAGCATCGTTTAAAAGCCTGTTGTGGTTCTTGCAGA TATGGCCCTCACTTGCCGCCTCCGTTTCCCGGTGCCGGGATACCGAGGAGGAAGATCGCGCCGCAGG AGGGGTCTGGCCGGCCGCGGCCTGAGCGGAGGCAGCCGCCGCGCGCACCGGCGGCGACGCGCCACC AGCCGACGCATGCGCGGCGGGGTGCTGCCCCTGTTAATCCCCCTGATCGCCGCGGCGATCGGCGCCG TGCCCGGGATCGCCTCCGTGGCCTTGCAAGCGTCCCAGAGGCATTGACAGACTTGCAAACTTGCAAA TATGGAAAAAAAAACCCCAATAAAAAAGTCTAGACTCTCACGCTCGCTTGGTCCTGTGACTATTTTGT AGAATGGAAGACATCAACTTTGCGTCGCTGGCCCCGCGTCACGGCTCGCGCCCGTTCCTGGGACACT GGAACGATATCGGCACCAGCAACATGAGCGGTGGCGCCTTCAGTTGGGGCTCTCTGTGGAGCGGCAT TAAAAGTATCGGGTCTGCCGTTAAAAATTACGGCTCCCGGGCCTGGAACAGCAGCACGGGCCAGATG TTGAGAGACAAGTTGAAAGAGCAGAACTTCCAGCAGAAGGTGGTGGAGGGCCTGGCCTCCGGCATC AACGGGGTGGTGGACCTGGCCAACCAGGCCGTGCAGAATAAGATCAACAGCAGACTGGACCCCCGG CCGCCGGTGGAGGAGGTGCCGCCGGCGCTGGAGACGGTGTCCCCCGATGGGCGTGGCGAGAAGCGC CCGCGGCCCGATAGGGAAGAGACCACTCTGGTCACGCAGACCGATGAGCCGCCCCCGTATGAGGAG GCCCTGAAGCAAGGTCTGCCCACCACGCGGCCCATCGCGCCCATGGCCACCGGGGTGGTGGGCCGCC ACACCCCCGCCACGCTGGACTTGCCTCCGCCCGCCGATGTGCCGCAGCAGCAGAAGGCGGCACAGCC GGGCCCGCCCGCGACCGCCTCCCGTTCCTCCGCCGGTCCTCTGCGCCGCGCGGCCAGCGGCCCCCGC GGGGGGGTCGCGAGGCACGGCAACTGGCAGAGCACGCTGAACAGCATCGTGGGTCTGGGGGTGCGG TCCGTGAAGCGCCGCCGATGCTACTGAATAGCTTAGCTAACGTGTTGTATGTGTGTATGCGCCCTATG TCGCCGCCAGAGGAGCTGCTGAGTCGCCGCCGTTCGCGCGCCCACCACCACCGCCACTCCGCCCCTC AAGATGGCGACCCCATCGATGATGCCGCAGTGGTCGTACATGCACATCTCGGGCCAGGACGCCTCGG AGTACCTGAGCCCCGGGCTGGTGCAGTTCGCCCGCGCCACCGAGAGCTACTTCAGCCTGAGTAACAA GTTTAGGAACCCCACGGTGGCGCCCACGCACGATGTGACCACCGACCGGTCTCAGCGCCTGACGCTG CGGTTCATTCCCGTGGACCGCGAGGACACCGCGTACTCGTACAAGGCGCGGTTCACCCTGGCCGTGG GCGACAACCGCGTGCTGGACATGGCCTCCACCTACTTTGACATCCGCGGGGTGCTGGACCGGGGTCC CACTTTCAAGCCCTACTCTGGCACCGCCTACAACTCCCTGGCCCCCAAGGGCGCTCCCAACTCCTGCG AGTGGGAGCAAGAGGAAACTCAGGCAGTTGAAGAAGCAGCAGAAGAGGAAGAAGAAGATGCTGAC GGTCAAGCTGAGGAAGAGCAAGCAGCTACCAAAAAGACTCATGTATATGCTCAGGCTCCCCTTTCTG GCGAAAAAATTAGTAAAGATGGTCTGCAAATAGGAACGGACGCTACAGCTACAGAACAAAAACCTA TTTATGCAGACCCTACATTCCAGCCCGAACCCCAAATCGGGGAGTCCCAGTGGAATGAGGCAGATGC TACAGTCGCCGGCGGTAGAGTGCTAAAGAAATCTACTCCCATGAAACCATGCTATGGTTCCTATGCA AGACCCACAAATGCTAATGGAGGTCAGGGTGTACTAACGGCAAATGCCCAGGGACAGCTAGAATCT CAGGTTGAAATGCAATTCTTTTCAACTTCTGAAAACGCCCGTAACGAGGCTAACAACATTCAGCCCA AATTGGTGCTGTATAGTGAGGATGTGCACATGGAGACCCCGGATACGCACCTTTCTTACAAGCCCGC AAAAAGCGATGACAATTCAAAAATCATGCTGGGTCAGCAGTCCATGCCCAACAGACCTAATTACATC GGCTTCAGAGACAACTTTATCGGCCTCATGTATTACAATAGCACTGGCAACATGGGAGTGCTTGCAG GTCAGGCCTCTCAGTTGAATGCAGTGGTGGACTTGCAAGACAGAAACACAGAACTGTCCTACCAGCT CTTGCTTGATTCCATGGGTGACAGAACCAGATACTTTTCCATGTGGAATCAGGCAGTGGACAGTTATG ACCCAGATGTTAGAATTATTGAAAATCATGGAACTGAAGACGAGCTCCCCAACTATTGTTTCCCTCTG GGTGGCATAGGGGTAACTGACACTTACCAGGCTGTTAAAACCAACAATGGCAATAACGGGGGCCAG GTGACTTGGACAAAAGATGAAACTTTTGCAGATCGCAATGAAATAGGGGTGGGAAACAATTTCGCTA TGGAGATCAACCTCAGTGCCAACCTGTGGAGAAACTTCCTGTACTCCAACGTGGCGCTGTACCTACC AGACAAGCTTAAGTACAACCCCTCCAATGTGGACATCTCTGACAACCCCAACACCTACGATTACATG AACAAGCGAGTGGTGGCCCCGGGGCTGGTGGACTGCTACATCAACCTGGGCGCGCGCTGGTCGCTGG ACTACATGGACAACGTCAACCCCTTCAACCACCACCGCAATGCGGGCCTGCGCTACCGCTCCATGCT CCTGGGCAACGGGCGCTACGTGCCCTTCCACATCCAGGTGCCCCAGAAGTTCTTTGCCATCAAGAAC CTCCTCCTCCTGCCGGGCTCCTACACCTACGAGTGGAACTTCAGGAAGGATGTCAACATGGTCCTCCA GAGCTCTCTGGGTAACGATCTCAGGGTGGACGGGGCCAGCATCAAGTTCGAGAGCATCTGCCTCTAC GCCACCTTCTTCCCCATGGCCCACAACACGGCCTCCACGCTCGAGGCCATGCTCAGGAACGACACCA ACGACCAGTCCTTCAATGACTACCTCTCCGCCGCCAACATGCTCTACCCCATACCCGCCAACGCCACC AACGTCCCCATCTCCATCCCCTCGCGCAACTGGGCGGCCTTCCGCGGCTGGGCCTTCACCCGCCTCAA GACCAAGGAGACCCCCTCCCTGGGCTCGGGATTCGACCCCTACTACACCTACTCGGGCTCCATTCCCT ACCTGGACGGCACCTTCTACCTCAACCACACTTTCAAGAAGGTCTCGGTCACCTTCGACTCCTCGGTC AGCTGGCCGGGCAACGACCGTCTGCTCACCCCCAACGAGTTCGAGATCAAGCGCTCGGTCGACGGGG AGGGCTACAACGTGGCCCAGTGCAACATGACCAAGGACTGGTTCCTGGTCCAGATGCTGGCCAACTA CAACATCGGCTACCAGGGCTTCTACATCCCAGAGAGCTACAAGGACAGGATGTACTCCTTCTTCAGG AACTTCCAGCCCATGAGCCGGCAGGTGGTGGACCAGACCAAGTACAAGGACTACCAGGAGGTGGGC ATCATCCACCAGCACAACAACTCGGGCTTCGTGGGCTACCTCGCCCCCACCATGCGCGAGGGACAGG CCTACCCCGCCAACTTCCCCTATCCGCTCATAGGCAAGACCGCGGTCGACAGCATCACCCAGAAAAA GTTCCTCTGCGACCGCACCCTCTGGCGCATCCCCTTCTCCAGCAACTTCATGTCCATGGGTGCGCTCT CGGACCTGGGCCAGAACTTGCTCTACGCCAACTCCGCCCACGCCCTCGACATGACCTTCGAGGTCGA CCCCATGGACGAGCCCACCCTTCTCTATGTTCTGTTCGAAGTCTTTGACGTGGTCCGGGTCCACCAGC CGCACCGCGGCGTCATCGAGACCGTGTACCTGCGTACGCCCTTCTCGGCCGGCAACGCCACCACCTA AAGAAGCAAGCCGCAGTCATCGCCGCCTGCATGCCGTCGGGTTCCACCGAGCAAGAGCTCAGGGCC ATCGTCAGAGACCTGGGATGCGGGCCCTATTTTTTGGGCACCTTCGACAAGCGCTTCCCTGGCTTTGT CTCCCCACACAAGCTGGCCTGCGCCATCGTCAACACGGCCGGCCGCGAGACCGGGGGCGTGCACTGG CTGGCCTTCGCCTGGAACCCGCGCTCCAAAACATGCTTCCTCTTTGACCCCTTCGGCTTTTCGGACCA GCGGCTCAAGCAAATCTACGAGTTCGAGTACGAGGGCTTGCTGCGTCGCAGCGCCATCGCCTCCTCG CCCGACCGCTGCGTCACCCTCGAAAAGTCCACCCAGACCGTGCAGGGGCCCGACTCGGCCGCCTGCG GTCTCTTCTGCTGCATGTTTCTGCACGCCTTTGTGCACTGGCCTCAGAGTCCCATGGACCGCAACCCC ACCATGAACTTGCTGACGGGGGTGCCCAACTCCATGCTCCAGAGCCCCCAGGTCGAGCCCACCCTGC GCCGCAACCAGGAGCAGCTCTACAGCTTCCTGGAGCGCCACTCGCCTTACTTCCGCCGCCACAGCGC ACAGATCAGGAGGGCCACCTCCTTCTGCCACTTGCAAGAGATGCAAGAAGGGTAATAACGATGTACA CACTTTTTTTCTCAATAAATGGCATCTTTTTATTTATACAAGCTCTCTGGGGTATTCATTTCCCACCAC CACCCGCCGTTGTCGCCATCTGGCTCTATTTAGAAATCGAAAGGGTTCTGCCGGGAGTCGCCGTGCGC CACGGGCAGGGACACGTTGCGATACTGGTAGCGGGTGCCCCACTTGAACTCGGGCACCACCAGGCG AGGCAGCTCGGGGAAGTTTTCGCTCCACAGGCTGCGGGTCAGCACCAGCGCGTTCATCAGGTCGGGC GCCGAGATCTTGAAGTCGCAGTTGGGGCCGCCGCCCTGCGCGCGCGAGTTGCGGTACACCGGGTTGC AGCACTGGAACACCAACAGCGCCGGGTGCTTCACGCTGGCCAGCACGCTGCGGTCGGAGATCAGCTC GGCGTCCAGGTCCTCCGCGTTGCTCAGCGCGAACGGGGTCATCTTGGGCACTTGCCGCCCCAGGAAG GGCGCGTGCCCCGGTTTCGAGTTGCAGTCGCAGCGCAGCGGGATCAGCAGGTGCCCGTGCCCGGACT CGGCGTTGGGGTACAGCGCGCGCATGAAGGCCTGCATCTGGCGGAAGGCCATCTGGGCCTTGGCGCC CTCCGAGAAGAACATGCCGCAGGACTTGCCCGAGAACTGGTTTGCGGGGCAGCTGGCGTCGTGCAGG CAGCAGCGCGCGTCGGTGTTGGCGATCTGCACCACGTTGCGCCCCCACCGGTTCTTCACGATCTTGGC CTTGGACGATTGCTCCTTCAGCGCGCGCTGCCCGTTCTCGCTGGTCACATCCATCTCGATCACATGTT CCTTGTTCACCATGCTGCTGCCGTGCAGACACTTCAGCTCGCCCTCCGTCTCGGTGCAGCGGTGCTGC CACAGCGCGCAGCCCGTGGGCTCGAAAGACTTGTAGGTCACCTCCGCGAAGGACTGCAGGTACCCCT GCAAAAAGCGGCCCATCATGGTCACGAAGGTCTTGTTGCTGCTGAAGGTCAGCTGCAGCCCGCGGTG CTCCTCGTTCAGCCAGGTCTTGCACACGGCCGCCAGCGCCTCCACCTGGTCGGGCAGCATCTTGAAGT TCACCTTCAGCTCATTCTCCACGTGGTACTTGTCCATCAGCGTGCGCGCCGCCTCCATGCCCTTCTCCC AGGCCGACACCAGCGGCAGGCTCACGGGGTTCTTCACCATCACCGTGGCCGCCGCCTCCGCCGCGCT TTCGCTTTCCGCCCCGCTGTTCTCTTCCTCTTCCTCCTCTTCCTCGCCGCCGCCCACTCGCAGCCCCCG CACCACGGGGTCGTCTTCCTGCAGGCGCTGCACCTTGCGCTTGCCGTTGCGCCCCTGCTTGATGCGCA CGGGCGGGTTGCTGAAGCCCACCATCACCAGCGCGGCCTCTTCTTGCTCGTCCTCGCTGTCCAGAATG ACCTCCGGGGAGGGGGGGTTGGTCATCCTCAGTACCGAGGCACGCTTCTTTTTCTTCCTGGGGGCGTT CGCCAGCTCCGCGGCTGCGGCCGCTGCCGAGGTCGAAGGCCGAGGGCTGGGCGTGCGCGGCACCAG CGCGTCCTGCGAGCCGTCCTCGTCCTCCTCGGACTCGAGACGGAGGCGGGCCCGCTTCTTCGGGGGC GCGCGGGGCGGCGGAGGCGGCGGCGGCGACGGAGACGGGGACGAGACATCGTCCAGGGTGGGTGG ACGGCGGGCCGCGCCGCGTCCGCGCTCGGGGGTGGTCTCGCGCTGGTCCTCTTCCCGACTGGCCATCT CCCACTGCTCCTTCTCCTATAGGCAGAAAGAGATCATGGAGTCTCTCATGCGAGTCGAGAAGGAGGA GGACAGCCTAACCGCCCCCTCTGAGCCCTCCACCACCGCCGCCACCACCGCCAATGCCGCCGCGGAC GACGCGCCCACCGAGACCACCGCCAGTACCACCCTCCCCAGCGACGCACCCCCGCTCGAGAATGAAG TGCTGATCGAGCAGGACCCGGGTTTTGTGAGCGGAGAGGAGGATGAGGTGGATGAGAAGGAGAAGG AGGAGGTCGCCGCCTCAGTGCCAAAAGAGGATAAAAAGCAAGACCAGGACGACGCAGATAAGGAT GAGACAGCAGTCGGGCGGGGGAACGGAAGCCATGATGCTGATGACGGCTACCTAGACGTGGGAGAC GACGTGCTGCTTAAGCACCTGCACCGCCAGTGCGTCATCGTCTGCGACGCGCTGCAGGAGCGCTGCG AAGTGCCCCTGGACGTGGCGGAGGTCAGCCGCGCCTACGAGCGGCACCTCTTCGCGCCGCACGTGCC CCCCAAGCGCCGGGAGAACGGCACCTGCGAGCCCAACCCGCGTCTCAACTTCTACCCGGTCTTCGCG GTACCCGAGGTGCTGGCCACCTACCACATCTTTTTCCAAAACTGCAAGATCCCCCTCTCCTGCCGCGC CAACCGCACCCGCGCCGACAAAACCCTGACCCTGCGGCAGGGCGCCCACATACCTGATATCGCCTCT CTGGAGGAAGTGCCCAAGATCTTCGAGGGTCTCGGTCGCGACGAGAAACGGGCGGCGAACGCTCTG CACGGAGACAGCGAAAACGAGAGTCACTCGGGGGTGCTGGTGGAGCTCGAGGGCGACAACGCGCGC CTGGCCGTACTCAAGCGCAGCATAGAGGTCACCCACTTTGCCTACCCGGCGCTCAACCTGCCCCCCA AGGTCATGAGTGTGGTCATGGGCGAGCTCATCATGCGCCGCGCCCAGCCCCTGGCCGCGGATGCAAA CTTGCAAGAGTCCTCCGAGGAAGGCCTGCCCGCGGTCAGCGACGAGCAGCTGGCGCGCTGGCTGGA GACCCGCGACCCCGCGCAGCTGGAGGAGCGGCGCAAGCTCATGATGGCCGCGGTGCTGGTCACCGT GGAGCTCGAGTGTCTGCAGCGCTTCTTCGCGGACCCCGAGATGCAGCGCAAGCTCGAGGAGACCCTG CACTACACCTTCCGCCAGGGCTACGTGCGCCAGGCCTGCAAGATCTCCAACGTGGAGCTCTGCAACC TGGTCTCCTACCTGGGCATCCTGCACGAGAACCGCCTCGGGCAGAACGTCCTGCACTCCACCCTCAA AGGGGAGGCGCGCCGCGACTACATCCGCGACTGCGCCTACCTCTTCCTCTGCTACACCTGGCAGACG GCCATGGGGGTCTGGCAGCAGTGCCTGGAGGAGCGCAACCTCAAGGAGCTGGAAAAGCTCCTCAAG CGCACCCTCAGGGACCTCTGGACGGGCTTCAACGAGCGCTCGGTGGCCGCCGCGCTGGCGGACATCA TCTTTCCCGAGCGCCTGCTCAAGACCCTGCAGCAGGGCCTGCCCGACTTCACCAGCCAGAGCATGCT GCAGAACTTCAGGACTTTCATCCTGGAGCGCTCGGGCATCCTGCCGGCCACTTGCTGCGCGCTGCCCA GCGACTTCGTGCCCATCAAGTACAGGGAGTGCCCGCCGCCGCTCTGGGGCCACTGCTACCTCTTCCA GCTGGCCAACTACCTCGCCTACCACTCGGACCTCATGGAAGACGTGAGCGGCGAGGGCCTGCTCGAG TGCCACTGCCGCTGCAACCTCTGCACGCCCCACCGCTCTCTAGTCTGCAACCCGCAGCTGCTCAGCGA GAGTCAGATTATCGGTACCTTCGAGCTGCAGGGTCCCTCGCCTGACGAGAAGTCCGCGGCTCCAGGG CTGAAACTCACTCCGGGGCTGTGGACTTCCGCCTACCTACGCAAATTTGTACCTGAGGACTACCACGC CCACGAGATCAGGTTCTACGAAGACCAATCCCGCCCGCCCAAGGCGGAGCTCACCGCCTGCGTCATC ACCCAGGGGCACATCCTGGGCCAATTGCAAGCCATCAACAAAGCCCGCCGAGAGTTCTTGCTGAAAA AGGGTCGGGGGGTGTACCTGGACCCCCAGTCCGGCGAGGAGCTAAACCCGCTACCCCCGCCGCCGCC CCAGCAGCGGGACCTTGCTTCCCAGGATGGCACCCAGAAAGAAGCAGCAGCCGCCGCCGCCGCCGC AGCCATACATGCTTCTGGAGGAAGAGGAGGAGGACTGGGACAGTCAGGCAGAGGAGGTTTCGGACG AGGAGCAGGAGGAGATGATGGAAGACTGGGAGGAGGACAGCAGCCTAGACGAGGAAGCTTCAGAG GCCGAAGAGGTGGCAGACGCAACACCATCGCCCTCGGTCGCAGCCCCCTCGCCGGGGCCCCTGAAAT CCTCCGAACCCAGCACCAGCGCTATAACCTCCGCTCCTCCGGCGCCGGCGCCACCCGCCCGCAGACC CAACCGTAGATGGGACACCACAGGAACCGGGGTCGGTAAGTCCAAGTGCCCGCCGCCGCCACCGCA GCAGCAGCAGCAGCAGCGCCAGGGCTACCGCTCGTGGCGCGGGCACAAGAACGCCATAGTCGCCTG CTTGCAAGACTGCGGGGGCAACATCTCTTTCGCCCGCCGCTTCCTGCTATTCCACCACGGGGTCGCCT TTCCCCGCAATGTCCTGCATTACTACCGTCATCTCTACAGCCCCTACTGCAGCGGCGACCCAGAGGCG GCAGCGGCAGCCACAGCGGCGACCACCACCTAGGAAGATATCCTCCGCGGGCAAGACAGCGGCAGC AGCGGCCAGGAGACCCGCGGCAGCAGCGGCGGGAGCGGTGGGCGCACTGCGCCTCTCGCCCAACGA ACCCCTCTCGACCCGGGAGCTCAGACACAGGATCTTCCCCACTTTGTATGCCATCTTCCAACAGAGCA GAGGCCAGGAGCAGGAGCTGAAAATAAAAAACAGATCTCTGCGCTCCCTCACCCGCAGCTGTCTGTA TCACAAAAGCGAAGATCAGCTTCGGCGCACGCTGGAGGACGCGGAGGCACTCTTCAGCAAATACTG CGCGCTCACTCTTAAAGACTAGCTCCGCGCCCTTCTCGAATTTAGGCGGGAGAAAACTACGTCATCG CCGGCCGCCGCCCAGCCCGCCCAGCCGAGATGAGCAAAGAGATTCCCACGCCATACATGTGGAGCTA CCAGCCGCAGATGGGACTCGCGGCGGGAGCGGCCCAGGACTACTCCACCCGCATGAACTACATGAG CGCGGGACCCCACATGATCTCACAGGTCAACGGGATCCGCGCCCAGCGAAACCAAATACTGCTGGA ACAGGCGGCCATCACCGCCACGCCCCGCCATAATCTCAACCCCCGAAATTGGCCCGCCGCCCTCGTG TACCAGGAAACCCCCTCCGCCACCACCGTACTACTTCCGCGTGACGCCCAGGCCGAAGTCCAGATGA CTAACTCAGGGGCGCAGCTCGCGGGCGGCTTTCGTCACGGGGCGCGGCCGCTCCGACCAGGTATAAG ACACCTGATGATCAGAGGCCGAGGTATCCAGCTCAACGACGAGTCGGTGAGCTCTTCGCTCGGTCTC CGTCCGGACGGAACTTTCCAGCTCGCCGGATCCGGCCGCTCTTCGTTCACGCCCCGCCAGGCGTACCT GACTCTGCAGACCTCGTCCTCGGAGCCCCGCTCCGGCGGCATCGGAACCCTCCAGTTCGTGGAGGAG TTCGTGCCCTCGGTCTACTTCAACCCCTTCTCGGGACCTCCCGGACGCTACCCCGACCAGTTCATTCC GAACTTTGACGCGGTGAAGGACTCGGCGGACGGCTACGACTGAATGTCAGGTGTCGAGGCAGAGCA GCTTCGCCTGAGACACCTCGAGCACTGCCGCCGCCACAAGTGCTTCGCCCGCGGTTCTGGTGAGTTCT GCTACTTTCAGCTACCCGAGGAGCATACCGAGGGGCCGGCGCACGGCGTCCGCCTGACCACCCAGGG CGAGGTTACCTGTTCCCTCATCCGGGAGTTTACCCTCCGTCCCCTGCTAGTGGAGCGGGAGCGGGGTC CCTGTGTCCTAACTATCGCCTGCAACTGCCCTAACCCTGGATTACATCAAGATCTTTGCTGTCATCTCT GTGCTGAGTTTAATAAACGCTGAGATCAGAATCTACTGGGGCTCCTGTCGCCATCCTGTGAACGCCA CCGTCTTCACCCACCCCGACCAGGCCCAGGCGAACCTCACCTGCGGTCTGCATCGGAGGGCCAAGAA GTACCTCACCTGGTACTTCAACGGCACCCCCTTTGTGGTTTACAACAGCTTCGACGGGGACGGAGTCT CCCTGAAAGACCAGCTCTCCGGTCTCAGCTACTCCATCCACAAGAACACCACCCTCCAACTCTTCCCT CCCTACCTGCCGGGAACCTACGAGTGCGTCACCGGCCGCTGCACCCACCTCACCCGCCTGATCGTAA ACCAGAGCTTTCCGGGAACAGATAACTCCCTCTTCCCCAGAACAGGAGGTGAGCTCAGGAAACTCCC CGGGGACCAGGGCGGAGACGTACCTTCGACCCTTGTGGGGTTAGGATTTTTTATTACCGGGTTGCTG GCTCTTTTAATCAAAGTTTCCTTGAGATTTGTTCTTTCCTTCTACGTGTATGAACACCTCAACCTCCAA TAACTCTACCCTTTCTTCGGAATCAGGTGACTTCTCTGAAATCGGGCTTGGTGTGCTGCTTACTCTGTT GATTTTTTTCCTTATCATACTCAGCCTTCTGTGCCTCAGGCTCGCCGCCTGCTGCGCACACATCTATAT CTACTGCTGGTTGCTCAAGTGCAGGGGTCGCCACCCAAGATGAACAGGTACATGGTCCTATCGATCC TAGGCCTGCTGGCCCTGGCGGCCTGCAGCGCCGCCAAAAAAGAGATTACCTTTGAGGAGCCCGCTTG CAATGTAACTTTCAAGCCCGAGGGTGACCAATGCACCACCCTCGTCAAATGCGTTACCAATCATGAG AGGCTGCGCATCGACTACAAAAACAAAACTGGCCAGTTTGCGGTCTATAGTGTGTTTACGCCCGGAG ACCCCTCTAACTACTCTGTCACCGTCTTCCAGGGCGGACAGTCTAAGATATTCAATTACACTTTCCCT TTTTATGAGTTATGCGATGCGGTCATGTACATGTCAAAACAGTACAACCTGTGGCCTCCCTCTCCCCA GGCGTGTGTGGAAAATACTGGGTCTTACTGCTGTATGGCTTTCGCAATCACTACGCTCGCTCTAATCT GCACGGTGCTATACATAAAATTCAGGCAGAGGCGAATCTTTATCGATGAAAAGAAAATGCCTTGATC GCTAACACCGGCTTTCTATCTGCAGAATGAATGCAATCACCTCCCTACTAATCACCACCACCCTCCTT GCGATTGCCCATGGGTTGACACGAATCGAAGTGCCAGTGGGGTCCAATGTCACCATGGTGGGCCCCG CCGGCAATTCCACCCTCATGTGGGAAAAATTTGTCCGCAATCAATGGGTTCATTTCTGCTCTAACCGA ATCAGTATCAAGCCCAGAGCCATCTGCGATGGGCAAAATCTAACTCTGATCAATGTGCAAATGATGG ATGCTGGGTACTATTACGGGCAGCGGGGAGAAATCATTAATTACTGGCGACCCCACAAGGACTACAT GCTGCATGTAGTCGAGGCACTTCCCACTACCACCCCCACTACCACCTCTCCCACCACCACCACCACTA CTACTACTACTACTACTACTACTACTACTACCACTACCGCTGCCCGCCATACCCGCAAAAGCACCATG ATTAGCACAAAGCCCCCTCGTGCTCACTCCCACGCCGGCGGGCCCATCGGTGCGACCTCAGAAACCA CCGAGCTTTGCTTCTGCCAATGCACTAACGCCAGCGCTCATGAACTGTTCGACCTGGAGAATGAGGA TGTCCAGCAGAGCTCCGCTTGCCTGACCCAGGAGGCTGTGGAGCCCGTTGCCCTGAAGCAGATCGGT GATTCAATAATTGACTCTTCTTCTTTTGCCACTCCCGAATACCCTCCCGATTCTACTTTCCACATCACG GGTACCAAAGACCCTAACCTCTCTTTCTACCTGATGCTGCTGCTCTGTATCTCTGTGGTCTCTTCCGCG CTGATGTTACTGGGGATGTTCTGCTGCCTGATCTGCCGCAGAAAGAGAAAAGCTCGCTCTCAGGGCC AACCACTGATGCCCTTCCCCTACCCCCCGGATTTTGCAGATAACAAGATATGAGCTCGCTGCTGACAC TAACCGCTTTACTAGCCTGCGCTCTAACCCTTGTCGCTTGCGACTCGAGATTCCACAATGTCACAGCT GTGGCAGGAGAAAATGTTACTTTCAACTCCACGGCCGATACCCAGTGGTCGTGGAGTGGCTCAGGTA GCTACTTAACTATCTGCAATAGCTCCACTTCCCCCGGCATATCCCCAACCAAGTACCAATGCAATGCC AGCCTGTTCACCCTCATCAACGCTTCCACCCTGGACAATGGACTCTATGTAGGCTATGTACCCTTTGG TGGGCAAGGAAAGACCCACGCTTACAACCTGGAAGTTCGCCAGCCCAGAACCACTACCCAAGCTTCT CCCACCACCACCACCACCACCACCATCACCAGCAGCAGCAGCAGCAGCAGCCACAGCAGCAGCAGC AGATTATTGACTTTGGTTTTGGCCAGCTCATCTGCCGCTACCCAGGCCATCTACAGCTCTGTGCCCGA AACCACTCAGATCCACCGCCCAGAAACGACCACCGCCACCACCCTACACACCTCCAGCGATCAGATG CCGACCAACATCACCCCCTTGGCTCTTCAAATGGGACTTACAAGCCCCACTCCAAAACCAGTGGATG CGGCCGAGGTCTCCGCCCTCGTCAATGACTGGGCGGGGCTGGGAATGTGGTGGTTCGCCATAGGCAT GATGGCGCTCTGCCTGCTTCTGCTCTGGCTCATCTGCTGCCTCCACCGCAGGCGAGCCAGACCCCCCA TCTATAGACCCATCATTGTCCTGAACCCCGATAATGATGGGATCCATAGATTGGATGGCCTGAAAAA CCTACTTTTTTCTTTTACAGTATGATAAATTGAGACATGCCTCGCATTTTCTTGTACATGTTCCTTCTCC CACCTTTTCTGGGGTGTTCTACGCTGGCCGCTGTGTCTCACCTGGAGGTAGACTGCCTCTCACCCTTC ACTGTCTACCTGCTTTACGGATTGGTCACCCTCACTCTCATCTGCAGCCTAATCACAGTAATCATCGC CTTCATCCAGTGCATTGATTACATCTGTGTGCGCCTCGCATACTTCAGACACCACCCGCAGTACCGAG ACAGGAACATTGCCCAACTTCTAAGACTGCTCTAATCATGCATAAGACTGTGATCTGCCTTCTGATCC TCTGCATCCTGCCCACCCTCACCTCCTGCCAGTACACCACAAAATCTCCGCGCAAAAGACATGCCTCC TGCCGCTTCACCCAACTGTGGAATATACCCAAATGCTACAACGAAAAGAGCGAGCTCTCCGAAGCTT GGCTGTATGGGGTCATCTGTGTCTTAGTTTTCTGCAGCACTGTCTTTGCCCTCATAATCTACCCCTACT TTGATTTGGGATGGAACGCGATCGATGCCATGAATTACCCCACCTTTCCCGCACCCGAGATAATTCCA CTGCGACAAGTTGTACCCGTTGTCGTTAATCAACGCCCCCCATCCCCTACGCCCACTGAAATCAGCTA CTTTAACCTAACAGGCGGAGATGACTGACGCCCTAGATCTAGAAATGGACGGCATCAGTACCGAGCA GCGTCTCCTAGAGAGGCGCAGGCAGGCGGCTGAGCAAGAGCGCCTCAATCAGGAGCTCCGAGATCT CGTTAACCTGCACCAGTGCAAAAGAGGCATCTTTTGTCTGGTAAAGCAGGCCAAAGTCACCTACGAG AAGACCGGCAACAGCCACCGCCTCAGTTACAAATTGCCCACCCAGCGCCAGAAGCTGGTGCTCATGG TGGGTGAGAATCCCATCACCGTCACCCAGCACTCGGTAGAGACCGAGGGGTGTCTGCACTCCCCCTG TCGGGGTCCAGAAGACCTCTGCACCCTGGTAAAGACCCTGTGCGGTCTCAGAGATTTAGTCCCCTTTA ACTAATCAAACACTGGAATCAATAAAAAGAATCACTTACTTAAAATCAGACAGCAGGTCTCTGTCCA GTTTATTCAGCAGCACCTCCTTCCCCTCCTCCCAACTCTGGTACTCCAAACGCCTTCTGGCGGCAAAC TTCCTCCACACCCTGAAGGGAATGTCAGATTCTTGCTCCTGTCCCTCCGCACCCACTATCTTCATGTTG TTGCAGATGAAGCGCACCAAAACGTCTGACGAGAGCTTCAACCCCGTGTACCCCTATGACACGGAAA GCGGCCCTCCCTCCGTCCCTTTCCTCACCCCTCCCTTCGTGTCTCCCGATGGATTCCAAGAAAGTCCCC CCGGGGTCCTGTCTCTGAACCTGGCCGAGCCCCTGGTCACTTCCCACGGCATGCTCGCCCTGAAAATG GGAAGTGGCCTCTCCCTGGACGACGCTGGCAACCTCACCTCTCAAGATATCACCACCGCTAGCCCTC CCCTCAAAAAAACCAAGACCAACCTCAGCCTAGAAACCTCATCCCCCCTAACTGTGAGCACCTCAGG CGCCCTCACCGTAGCAGCCGCCGCTCCCCTGGCGGTGGCCGGCACCTCCCTCACCATGCAATCAGAG GCCCCCCTGACAGTACAGGATGCAAAACTCACCCTGGCCACCAAAGGCCCCCTGACCGTGTCTGAAG GCAAACTGGCCTTGCAAACATCGGCCCCGCTGACGGCCGCTGACAGCAGCACCCTCACAGTCAGTGC CACACCACCCCTTAGCACAAGCAATGGCAGCTTGGGTATTGACATGCAAGCCCCCATTTACACCACC AATGGAAAACTAGGACTTAACTTTGGCGCTCCCCTGCATGTGGTAGACAGCCTAAATGCACTGACTG TAGTTACTGGCCAAGGTCTTACGATAAACGGAACAGCCCTACAAACTAGAGTCTCAGGTGCCCTCAA CTATGACACATCAGGAAACCTAGAATTGAGAGCTGCAGGGGGTATGCGAGTTGATGCAAATGGTCA ACTTATCCTTGATGTAGCTTACCCATTTGATGCACAAAACAATCTCAGCCTTAGGCTTGGACAGGGAC CCCTGTTTGTTAACTCTGCCCACAACTTGGATGTTAACTACAACAGAGGCCTCTACCTGTTCACATCT GGAAATACCAAAAAGCTAGAAGTTAATATCAAAACAGCCAAGGGTCTCATTTATGATGACACTGCTA TAGCAATCAATGCGGGTGATGGGCTACAGTTTGACTCAGGCTCAGATACAAATCCATTAAAAACTAA ACTTGGATTAGGACTGGATTATGACTCCAGCAGAGCCATAATTGCTAAACTGGGAACTGGCCTAAGC TTTGACAACACAGGTGCCATCACAGTAGGCAACAAAAATGATGACAAGCTTACCTTGTGGACCACAC CAGACCCATCCCCTAACTGTAGAATCTATTCAGAGAAAGATGCTAAATTCACACTTGTTTTGACTAAA TGCGGCAGTCAGGTGTTGGCCAGCGTTTCTGTTTTATCTGTAAAAGGTAGCCTTGCGCCCATCAGTGG CACAGTAACTAGTGCTCAGATTGTCCTCAGATTTGATGAAAATGGAGTTCTACTAAGCAATTCTTCCC TTGACCCTCAATACTGGAACTACAGAAAAGGTGACCTTACAGAGGGCACTGCATATACCAACGCAGT GGGATTTATGCCCAACCTCACAGCATACCCAAAAACACAGAGCCAAACTGCTAAAAGCAACATTGTA AGTCAGGTTTACTTGAATGGGGACAAATCCAAACCCATGACCCTCACCATTACCCTCAATGGAACTA ATGAAACAGGAGATGCCACAGTAAGCACTTACTCCATGTCATTCTCATGGAACTGGAATGGAAGTAA TTACATTAATGAAACGTTCCAAACCAACTCCTTCACCTTCTCCTACATCGCCCAAGAATAAAAAGCAT GACGCTGTTGATTTGATTCAATGTGTTTCTGTTTTATTTTCAAGCACAACAAAATCATTCAAGTCATTC TTCCATCTTAGCTTAATAGACACAGTAGCTTAATAGACCCAGTAGTGCAAAGCCCCATTCTAGCTTAT AACTAGTGGAGAAGTACTCGCCTACATGGGGGTAGAGTCATAATCGTGCATCAGGATAGGGCGGTG GTGCTGCAGCAGCGCGCGAATAAACTGCTGCCGCCGCCGCTCCGTCCTGCAGGAATACAACATGGCA GTGGTCTCCTCAGCGATGATTCGCACCGCCCGCAGCATAAGGCGCCTTGTCCTCCGGGCACAGCAGC GCACCCTGATCTCACTTAAATCAGCACAGTAACTGCAGCACAGCACCACAATATTGTTCAAAATCCC ACAGTGCAAGGCGCTGTATCCAAAGCTCATGGCGGGGACCACAGAACCCACGTGGCCATCATACCAC AAGCGCAGGTAGATTAAGTGGCGACCCCTCATAAACACGCTGGACATAAACATTACCTCTTTTGGCA TGTTGTAATTCACCACCTCCCGGTACCATATAAACCTCTGATTAAACATGGCGCCATCCACCACCATC CTAAACCAGCTGGCCAAAACCTGCCCGCCGGCTATACACTGCAGGGAACCGGGACTGGAACAATGA CAGTGGAGAGCCCAGGACTCGTAACCATGGATCATCATGCTCGTCATGATATCAATGTTGGCACAAC ACAGGCACACGTGCATACACTTCCTCAGGATTACAAGCTCCTCCCGCGTTAGAACCATATCCCAGGG AACAACCCATTCCTGAATCAGCGTAAATCCCACACTGCAGGGAAGACCTCGCACGTAACTCACGTTG TGCATTGTCAAAGTGTTACATTCGGGCAGCAGCGGATGATCCTCCAGTATGGTAGCGCGGGTTTCTGT CTCAAAAGGAGGTAGACGATCCCTACTGTACGGAGTGCGCCGAGACAACCGAGATCGTGTTGGTCGT AGTGTCATGCCAAATGGAACGCCGGACGTAGTCATATTTCCTGAAGTCTTAGATCTCTCAACGCAGC ACCAGCACCAACACTTCGCAGTGTAAAAGGCCAAGTGCCGAGAGAGTATATATAGGAATAAAAAGT GACGTAAACGGGCAAAGTCCAAAAAACGCCCAGAAAAACCGCACGCGAACCTACGCCCCGAAACGA AAGCCAAAAAACACTAGACACTCCCTTCCGGCGTCAACTTCCGCTTTCCCACGCTACGTCACTTGCCC CAGTCAAACAAACTACATATCCCGAACTTCCAAGTCGCCACGCCCAAAACACCGCCTACACCTCCCC GCCCGCCGGCCCGCCCCCAAACCCGCCTCCCGCCCCGCGCCCCGCCCCGCGCCGCCCATCTCATTATC ATATTGGCTTCAATCCAAAATAAGGTATATTATTGATGATG Polynucleotide sequence encoding the CASI promoter SEQ ID NO: 12 GGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCA TTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGT GGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCT ATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCC TACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCT TCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGC AGCGATGGGGGCGGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGG CGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTAT GGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCTCCCTATCAGTGATAGAGATCTCC CTATCAGTGATAGAGATCGTCGACGAGCTCGCGGCGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCC GTGCCCCGCTCCGCCGCCGCCTCGCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTAAAACAGG TAAGTCCGGCCTCCGCGCCGGGTTTTGGCGCCTCCCGCGGGCGCCCCCCTCCTCACGGCGAGCGCTGC CACGTCAGACGAAGGGCGCAGCGAGCGTCCTGATCCTTCCGCCCGGACGCTCAGGACAGCGGCCCGC TGCTCATAAGACTCGGCCTTAGAACCCCAGTATCAGCAGAAGGACATTTTAGGACGGGACTTGGGTG ACTCTAGGGCACTGGTTTTCTTTCCAGAGAGCGGAACAGGCGAGGAAAAGTAGTCCCTTCTCGGCGA TTCTGCGGAGGGATCTCCGTGGGGCGGTGAACGCCGATGATGCCTCTACTAACCATGTTCATGTTTTC TTTTTTTTTCTACAGGTCCTGGGTGACGAACAG Ad5orf6 primer 1 polynucleotide sequence SEQ ID NO: 13 ATACGGACTAGTGGAGAAGTACTCGCCTACATG Ad5orf6 primer 2 polynucleotide sequence SEQ ID NO: 14 ATACGGAAGATCTAAGACTTCAGGAAATATGACTAC BAC/CHAd155 ΔE1_TetO hCMV RpsL-Kana primer 1 polynucleotide sequence SEQ ID NO: 15 ATTCAGTGTACAGGCGCGCCAAAGCATGACGCTGTTGATTTGATTC BAC/CHAd155 ΔE1_TetO hCMV RpsL-Kana (#1375) primer 2 polynucleotide sequence SEQ ID NO: 16 ACTAGGACTAGTTATAAGCTAGAATGGGGCTTTGC 1021-FW E4 Del Step1 primer polynucleotide sequence SEQ ID NO: 17 TTAATAGACACAGTAGCTTAATAGACCCAGTAGTGCAAAGCCCCATTCTAGCTTATAACCCCTATTTG TTTATTTTTCT 1022-RW E4 Del Step1 primer polynucleotide sequence SEQ ID NO: 18 ATATATACTCTCTCGGCACTTGGCCTTTTACACTGCGAAGTGTTGGTGCTGGTGCTGCGTTGAGAGAT CTTTATTTGTTAACTGTTAATTGTC 1025-FW E4 Del Step2 primer polynucleotide sequence SEQ ID NO: 19 TTAATAGACACAGTAGCTTAATA 1026-RW E4 Del Step2 primer polynucleotide sequence SEQ ID NO: 20 GGAAGGGAGTGTCTAGTGTT 91-SubMonte FW primer polynucleotide sequence SEQ ID NO: 21 CAATGGGCGTGGATAGCGGTTTGAC 90-BghPolyA RW primer polynucleotide sequence SEQ ID NO: 22 CAGCATGCCTGCTATTGTC CMVfor primer polynucleotide sequence SEQ ID NO: 23 CATCTACGTATTAGTCATCGCTATTACCA CMVrev primer polynucleotide sequence SEQ ID NO: 24 GACTTGGAAATCCCCGTGAGT CMVFAM-TAMRA qPCR probe polynucleotide sequence SEQ ID NO: 25 ACATCAATGGGCGTGGATAGCGGTT Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) polynucleotide sequence SEQ ID NO: 26 TAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTAC GCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTC CTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCG TGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTT TCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTG CTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTTC CTTGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCC TCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTC GCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCT ChAd3 fiber amino acid sequence SEQ ID NO: 27 MKRTKTSDESFNPVYPYDTESGPPSVPFLTPPFVSPDGFQESPPGVLSLNLAEPLVTSHGMLALKMGSGLS LDDAGNLTSQDITTASPPLKKTKTNLSLETSSPLTVSTSGALTVAAAAPLAVAGTSLTMQSEAPLTVQDAK LTLATKGPLTVSEGKLALQTSAPLTAADSSTLTVSATPPINVSSGSLGLDMEDPMYTHDGKLGIRIGGPLR VVDSLHTLTVVTGNGLTVDNNALQTRVTGALGYDTSGNLQLRAAGGMRIDANGQLILNVAYPFDAQNN LSLRLGQGPLYINTDHNLDLNCNRGLTTTTTNNTKKLETKISSGLDYDTNGAVIIKLGTGLSFDNTGALTV GNTGDDKLTLWTTPDPSPNCRIHSDKDCKFTLVLTKCGSQILASVAALAVSGNLASITGTVASVTIFLRFD QNGVLMENSSLDRQYWNFRNGNSTNAAPYTNAVGFMPNLAAYPKTQSQTAKNNIVSQVYLNGDKSKP MTLTITLNGTNESSETSQVSHYSMSFTWAWESGQYATETFATNSFTFSYIAEQ PanAd3 fiber amino acid sequence SEQ ID NO: 28 MKRAKTSDETFNPVYPYDTENGPPSVPFLTPPFVSPDGFQESPPGVLSLRLSEPLVTSHGMLALKMGNGLS LDDAGNLTSQDVTTVTPPLKKTKTNLSLQTSAPLTVSSGSLTVAAAAPLAVAGTSLTMQSQAPLTVQDAK LGLATQGPLTVSEGKLTLQTSAPLTAADSSTLTVGTTPPISVSSGSLGLDMEDPMYTHDGKLGIRIGGPLQ VVDSLHTLTVVTGNGITVANNALQTKVAGALGYDSSGNLELRAAGGMRINTGGQLILDVAYPFDAQNNL SLRLGQGPLYVNTNHNLDLNCNRGLTTTTSSNTTKLETKIDSGLDYNANGAIIAKLGTGLTFDNTGAITVG NTGDDKLTLWTTPDPSPNCRIHADKDKFTLVLTKCGSQILASVAALAVSGNLSSMTGTVSSVTIFLRFDQN GVLMENSSLDKEYWNFRNGNSTNATPYTNAVGFMPNLSAYPKTQSQTAKNNIVSEVYLHGDKSKPMILT ITLNGTNESSETSQVSHYSMSFTWSWDSGKYATETFATNSFTFSYIAEQ ChAd17 fiber amino acid sequence SEQ ID NO: 29 MKRTKTSDESFNPVYPYDTESGPPSVPFLTPPFVSPDGFQESPPGVLSLNLAEPLVTSHGMLALKMGSGLS LDDAGNLTSQDITSTTPPLKKTKTNLSLETSSPLTVSTSGALTVAAAAPLAVAGTSLTMQSEAPLAVQDAK LTLATKGPLTVSEGKLALQTSAPLTAADSSTLTVSSTPPISVSSGSLGLDMEDPMYTHDGKLGIRIGGPLRV VDSLHTLTVVTGNGLTVDNNALQTRVTGALGYDTSGNLQLRAAGGMRIDANGQLILDVAYPFDAQNNL SLRLGQGPLYVNTDHNLDLNCNRGLTTTTTNNTKKLETKISSGLDYDTNGAVIIKLGTGLSFDNTGALTV GNTGDDKLTLWTTPDPSPNCRIHSDKDCKFTLVLTKCGSQILASVAALAVSGNLASITGTVASVTIFLRFD QNGVLMENSSLDKQYWNFRNGNSTNAAPYTNAVGFMPNLAAYPKTQSQTAKNNIVSQVYLNGDKSKP MTLTITLNGTNESSETSQVSHYSMSFTWAWESGQYATETFATNSFTFSYIAEQ ChAd19 fiber amino acid sequence SEQ ID NO: 30 MKRTKTSDKSFNPVYPYDTENGPPSVPFLTPPFVSPDGFQESPPGVLSLNLAEPLVTSHGMLALKMGSGLS LDDAGNLTSQDVTTTTPPLKKTKTNLSLETSAPLTVSTSGALTLAAAAPLAVAGTSLTMQSEAPLTVQDA KLTLATKGPLTVSEGKLALQTSAPLTAADSSTLTVSATPPISVSSGSLGLDMEDPMYTHDGKLGIRTGGPLR VVDSLHTLTVVTGNGIAVDNNALQTRVTGALGYDTSGNLQLRAAGGMRIDANGQLILDVAYPFDAQNN LSLRLGQGPLYVNTDHNLDLNCNRGLTTTTTNNTKKLETKIGSGLDYDTNGAVIIKLGTGVSFDSTGALS VGNTGDDKLTLWTTPDPSPNCRIHSDKDCKFTLVLTKCGSQILASVAALAVSGNLASITGTVSSVTIFLRFD QNGVLMENSSLDKQYWNFRNGNSTNATPYTNAVGFMPNLAAYPKTQSQTAKNNIVSQVYLNGDKSKP MTLTITLNGTNESSETSQVSHYSMSFTWAWESGQYATETFATNSFTFSYIAEQ ChAd24 fiber amino acid sequence SEQ ID NO: 31 MKRTKTSDESFNPVYPYDTENGPPSVPFLTPPFVSPDGFQESPPGVLSLNLAEPLVTSHGMLALKMGSGLS LDDAGNLTSQDVTTTTPPLKKTKTNLSLETSAPLTVSTSGALTLAAAAPLAVAGTSLTMQSEAPLTVQDA KLTLATKGPLTVSEGKLALQTSAPLTAADSSTLTVSATPPINVSSGSLGLDMENPMYTHDGKLGIRTGGPL RVVDSLHTLTVVTGNGIAVDNNALQTRVTGALGYDTSGNLQLRAAGGMRIDANGQLILDVAYPFDAQN NLSLRLGQGPLYVNTDHNLDLNCNRGLTTTTTNNTKKLETKIGSGLDYDTNGAVIIKLGTGVSFDSTGAL SVGNTGDDKLTLWTTPDPSPNCRIHSDKDCKFTLVLTKCGSQILASVAALAVSGNLASITGTVSSVTIFLRF DQNGVLMENSSLDKQYWNFRNGNSTNATPYTNAVGFMPNLAAYPKTQSQTAKNNIVSQVYLNGDKSKP MILTITLNGTNESSETSQVSHYSMSFTWAWESGQYATETFATNSFTFSYIAEQ ChAd11 fiber amino acid sequence SEQ ID NO: 32 MKRTKTSDESFNPVYPYDTENGPPSVPFLTPPFVSPDGFQESPPGVLSLNLAEPLVTSHGMLALKMGSGLS LDDAGNLTSQDVTTTTPPLKKTKTNLSLETSAPLTVSTSGALTLAAAVPLAVAGTSLTMQSEAPLTVQDA KLTLATKGPLTVSEGKLALQTSAPLTAADSSTLTISATPPLSTSNGSLGIDMQAPIYTTNGKLGLNFGAPLH VVDSLNALTVVTGQGLTINGTALQTRVSGALNYDSSGNLELRAAGGMRVDANGKLILDVAYPFDAQNN LSLRLGQGPLFVNSAHNLDVNYNRGLYLFTSGNTKKLEVNIKTAKGLIYDDTAIAINPGDGLEFGSGSDTN PLKTKLGLGLEYDSSRAIIAKLGTGLSFDNTGAITVGNKNDDKLTLWTTPDPSPNCRIYSEKDAKFTLVLT KCGSQVLASVSVLSVKGSLAPISGTVTSAQIILRFDENGVLLSNSSLDPQYWNYRKGDLTEGTAYTNAVGF MPNLTAYPKTQSQTAKSNIVSQVYLNGDKSKPMILTITLNGTNETGDATVSTYSMSFSWNWNGSNYINET FQTNSFTFSYIAQE ChAd20 fiber amino acid sequence SEQ ID NO: 33 MKRTKTSDESFNPVYPYDTESGPPSVPFLTPPFVSPDGFQESPPGVLSLNLAEPLVTSHGMLALKMGSGLS LDDAGNLTSQDITTASPPLKKTKTNLSLETSSPLTVSTSGALTVAAAAPLAVAGTSLTMQSEAPLTVQDAK LTLATKGPLTVSEGKLALQTSAPLTAADSSTLTVSATPPLSTSNGSLGIDMQAPIYTTNGKLGLNFGAPLH VVDSLNALTVVTGQGLTINGTALQTRVSGALNYDTSGNLELRAAGGMRVDANGQLILDVAYPFDAQNN LSLRLGQGPLFVNSAHNLDVNYNRGLYLFTSGNTKKLEVNIKTAKGLIYDDTAIAINAGDGLQFDSGSDT NPLKTKLGLGLDYDSSRAIIAKLGTGLSFDNTGAITVGNKNDDKLTLWTTPDPSPNCRIYSEKDAKFTLVL TKCGSQVLASVSVLSVKGSLAPISGTVTSAQIVLRFDENGVLLSNSSLDPQYWNYRKGDLTEGTAYTNAV GFMPNLTAYPKTQSQTAKSNIVSQVYLNGDKSKPMTLTITLNGTNETGDATVSTYSMSFSWNWNGSNYI NETFQTNSFTFSYIAQE ChAd31 fiber amino acid sequence SEQ ID NO: 34 MKRTKTSDESFNPVYPYDTESGPPSVPFLTPPFVSPDGFQESPPGVLSLNLAEPLVTSHGMLALKMGSGLS LDDAGNLTSQDITTASPPLKKTKTNLSLETSSPLTVSTSGALTVAAAAPLAVAGTSLTMQSEAPLTVQDAK LTLATKGPLTVSEGKLALQTSAPLTAADSSTLTVSATPPLSTSNGSLGIDMQAPIYTTNGKLGLNFGAPLH VVDSLNALTVVTGQGLTINGTALQTRVSGALNYDTSGNLELRAAGGMRVDANGQLILDVAYPFDAQNN LSLRLGQGPLFVNSAHNLDVNYNRGLYLFTSGNTKKLEVNIKTAKGLIYDDTAIAINAGDGLQFDSGSDT NPLKTKLGLGLDYDSSRAIIAKLGTGLSFDNTGAITVGNKNDDKLTLWTTPDPSPNCRIYSEKDAKFTLVL TKCGSQVLASVSVLSVKGSLAPISGTVTSAQIVLRFDENGVLLSNSSLDPQYWNYRKGDLTEGTAYTNAV GFMPNLTAYPKTQSQTAKSNIVSQVYLNGDKSKPMTLTITLNGTNETGDATVSTYSMSFSWNWNGSNYI NETFQTNSFTFSYIAQE PanAd1 fiber amino acid sequence SEQ ID NO: 35 MKRAKTSDETFNPVYPYDTENGPPSVPFLTPPFVSPDGFQESPPGVLSLRLSEPLVTSHGMLALKMGNGLS LDDAGNLTSQDVTTVTPPLKKTKTNLSLQTSAPLTVSSGSLTVAAAAPLAVAGTSLTMQSQAPLTVQDAK LGLATQGPLTVSEGKLTLQTSAPLTAADSSTLTVSATPPLSTSNGSLSIDMQAPIYTTNGKLALNIGAPLHV VDTLNALTVVTGQGLTINGRALQTRVTGALSYDTEGNIQLQAGGGMRIDNNGQLILNVAYPFDAQNNLS LRLGQGPLIVNSAHNLDLNLNRGLYLFTSGNTKKLEVNIKTAKGLFYDGTAIAINAGDGLQFGSGSDTNPL QTKLGLGLEYDSNKAIITKLGTGLSFDNTGAITVGNKNDDKLTLWTTPDPSPNCRINSEKDAKLTLVLTKC GSQVLASVSVLSVKGSLAPISGTVTSAQIVLRFDENGVLLSNSSLDPQYWNYRKGDSTEGTAYTNAVGFM PNLTAYPKTQSQTAKSNIVSQVYLNGDKTKPMTLTITLNGTNETGDATVSTYSMSFSWNWNGSNYINDTF QTNSFTFSYIAQE PanAd2 fiber amino acid sequence SEQ ID NO: 36 MKRAKTSDETFNPVYPYDTENGPPSVPFLTPPFVSPDGFQESPPGVLSLRLSEPLVTSHGMLALKMGNGLS LDDAGNLTSQDVTTVTPPLKKTKTNLSLQTSAPLTVSSGSLTVAAAAPLAVAGTSLTMQSQAPLTVQDAK LGLATQGPLTVSEGKLTLQTSAPLTAADSSTLTVSATPPLSTSNGSLSIDMQAPIYTTNGKLALNIGAPLHV VDTLNALTVVTGQGLTINGRALQTRVTGALSYDTEGNIQLQAGGGMRIDNNGQLILNVAYPFDAQNNLS LRLGQGPLIVNSAHNLDLNLNRGLYLFTSGNTKKLEVNIKTAKGLFYDGTAIAINAGDGLQFGSGSDTNPL QTKLGLGLEYDSNKAIITKLGTGLSFDNTGAITVGNKNDDKLTLWTTPDPSPNCRINSEKDAKLTLVLTKC GSQVLASVSVLSVKGSLAPISGTVTSAQIVLRFDENGVLLSNSSLDPQYWNYRKGDSTEGTAYTNAVGFM PNLTAYPKTQSQTAKSNIVSQVYLNGDKTKPMTLTITLNGTNETGDATVSTYSMSFSWNWNGSNYINDTF QTNSFTFSYIAQE RSV FΔTM-N-M2-1 amino acid sequence SEQ ID NO: 37 MELLILKANAITTILTAVTFCFASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIELSNIKENKCNGTD AKVKLIKQELDKYKNAVTELQLLMQSTPATNNRARRELPRFMNYTLNNAKKTNVTLSKKRKRRFLGFLL GVGSAIASGVAVSKVLHLEGEVNKIKSALLSTNKAVVSLSNGVSVLTSKVLDLKNYIDKQLLPIVNKQSCS ISNIETVIEFQQKNNRLLEITREFSVNAGVTTPVSTYMLTNSELLSLNDMPITNDQKKLMSNNVQIVRQQSY SIMSIIKEEVLAYVVQLPLYGVIDTPCWKLHTSPLCTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAET CKVQSNRVFCDTMNSLTLPSEVNLCNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKTKCTASNKN RGIIKTFSNGCDYVSNKGVDTVSVGNTLYYVNKQEGKSLYVKGEPIINFYDPLVFPSDEFDASISQVNEKIN QSLAFIRKSDELLHNVNAGKSTTNRKRRAPVKQTLNFDLLKLAGDVESNPGPMALSKVKLNDTLNKDQL LSSSKYTIQRSTGDSIDTPNYDVQKHINKLCGMLLITEDANHKFTGLIGMLYAMSRLGREDTIKILRDAGY HVKANGVDVTTHRQDINGKEMKFEVLTLASLTTEIQINIEIESRKSYKKMLKEMGEVAPEYRHDSPDCGM IILCIAALVITKLAAGDRSGLTAVIRRANNVLKNEMKRYKGLLPKDIANS FYEVFEKYPHFIDVFVHFGIAQSSTRGGSRVEGIFAGLFMNAYGAGQVMLRWGVLAKSVKNIMLGHASV QAEMEQVVEVYEYAQKLGGEAGFYHILNNPKASLLSLTQFPHFSSVVLGNAAGLGIMGEYRGTPRNQDL YDAAKAYAEQLKENGVINYSVLDLTAEELEAIKHQLNPKDNDVELGGGGSGGGGMSRRNPCKNFIRGHC LNGKRCHFSHNYFEWPPHALLVRQNFMLNRILKSMDKSIDTLSEISGAAELDRTEEYALGVVGVLESYIGS INNITKQSACVAMSKLLTELNSDDIKKLRDNEELNSPKIRVYNTVISYIESNRKNNKQTIHLLKRLPADVLK KTIKNTLDIHKSITINNPKESTVSDTNDHAKNNDTT HIV Gag polynucleotide sequence SEQ ID NO: 38 ATGGGTGCTAGGGCTTCTGTGCTGTCTGGTGGTGAGCTGGACAAGTGGGAGAAGATCAGGCTGAGGC CTGGTGGCAAGAAGAAGTACAAGCTAAAGCACATTGTGTGGGCCTCCAGGGAGCTGGAGAGGTTTG CTGTGAACCCTGGCCTGCTGGAGACCTCTGAGGGGTGCAGGCAGATCCTGGGCCAGCTCCAGCCCTC CCTGCAAACAGGCTCTGAGGAGCTGAGGTCCCTGTACAACACAGTGGCTACCCTGTACTGTGTGCAC CAGAAGATTGATGTGAAGGACACCAAGGAGGCCCTGGAGAAGATTGAGGAGGAGCAGAACAAGTCC AAGAAGAAGGCCCAGCAGGCTGCTGCTGGCACAGGCAACTCCAGCCAGGTGTCCCAGAACTACCCC ATTGTGCAGAACCTCCAGGGCCAGATGGTGCACCAGGCCATCTCCCCCCGGACCCTGAATGCCTGGG TGAAGGTGGTGGAGGAGAGGCCTTCTCCCCTGAGGTGATCCCCATGTTCTCTGCCCTGTCTGAGGGTG CCACCCCCCAGGACCTGAACACCATGCTGAACACAGTGGGGGGCCATCAGGCTGCCATGCAGATGCT GAAGGAGACCATCAATGAGGAGGCTGCTGAGTGGGACAGGCTGCATCCTGTGCACGCTGGCCCCATT GCCCCCGGCCAGATGAGGGAGCCCAGGGGCTCTGACATTGCTGGCACCACCTCCACCCTCCAGGAGC AGATTGGCTGGATGACCAACAACCCCCCCATCCCTGTGGGGGAAATCTACAAGAGGTGGATCATCCT GGGCCTGAACAAGATTGTGAGGATGTACTCCCCCACCTCCATCCTGGACATCAGGCAGGGCCCCAAG GAGCCCTTCAGGGACTATGTGGACAGGTTCTACAAGACCCTGAGGGCTGAGCAGGCCTCCCAGGAGG TGAAGAACTGGATGACAGAGACCCTGCTGGTGCAGAATGCCAACCCTGACTGCAAGACCATCCTGAA GGCCCTGGGCCCTGCTGCCACCCTGGAGGAGATGATGACAGCCTGCCAGGGGGTGGGGGGCCCTGGT CACAAGGCCAGGGTGCTGGCTGAGGCCATGTCCCAGGTGACCAACTCCGCCACCATCATGATGCAGA GGGGCAACTTCAGGAACCAGAGGAAGACAGTGAAGTGCTTCAACTGTGGCAAGGTGGGCCACATTG CCAAGAACTGTAGGGCCCCCAGGAAGAAGGGCTGCTGGAAGTGTGGCAAGGAGGGCCACCAGATGA AGGACTGCAATGAGAGGCAGGCCAACTTCCTGGGCAAAATCTGGCCCTCCCACAAGGGCAGGCCTG GCAACTTCCTCCAGTCCAGGCCTGAGCCCACAGCCCCTCCCGAGGAGTCCTTCAGGTTTGGGGAGGA GAAGACCACCCCCAGCCAGAAGCAGGAGCCCATTGACAAGGAGCTGTACCCCCTGGCCTCCCTGAG GTCCCTGTTTGGCAACGACCCCTCCTCCCAGTAA

Claims

1-42. (canceled)

43. A recombinant chimpanzee adenovirus ChAd155 comprising a nucleic acid sequence encoding a heterologous protein wherein:

(a) the E1 and E4 regions of chimpanzee adenovirus ChAd155 are deleted;
(b) E4orf6 of human adenovirus Ad5 is inserted;
(c) the nucleic acid sequence is operatively linked to one or more sequences which direct expression of said heterologous protein in a host cell; and
(d) the heterologous protein is an antigenic protein or fragment thereof derived from a virus and is selected from fusion protein (F), the attachment protein (G), the matrix protein (M2), and the nucleoprotein (N) of respiratory syncytial virus (RSV).

44. A composition comprising the recombinant chimpanzee adenovirus ChAd155 vector according to claim 43, and a pharmaceutically acceptable excipient.

45. The recombinant chimpanzee adenovirus ChAd155 according to claim 43, wherein the nucleic acid sequence encoding a heterologous protein encodes an RSV FΔTM antigen, an RSV M2-1 antigen and an N antigen.

46. The recombinant chimpanzee adenovirus ChAd155 according to claim 43, wherein the nucleic acid sequence encoding a heterologous protein encodes a sequence according to SEQ ID NO: 37.

47. The recombinant chimpanzee adenovirus ChAd155 according to claim 43, wherein the recombinant adenovirus is replication-incompetent.

48. The recombinant chimpanzee adenovirus ChAd155 according to claim 43, wherein the adenovirus is capable of infecting a mammalian cell.

49. The composition according to claim 44, further comprising at least one adjuvant selected from inorganic adjuvants, organic adjuvants, oil-based adjuvants, cytokines, particulate adjuvants, virosomes, bacterial adjuvants, synthetic adjuvants, synthetic polynucleotides adjuvants, and immunostimulatory oligonucleotides containing unmethylated CpG dinucleotides (“CpG”).

50. The composition according to claim 49, wherein the adjuvant is a 3D-MPL, QS21, or a mixture thereof.

51. A method of treatment or prophylaxis of respiratory syncytial virus (RSV) infection comprising administering to a patient in need thereof the recombinant chimpanzee vector ChAd155, of claim 43.

52. A method of treatment or prophylaxis of respiratory syncytial virus (RSV) infection comprising administering to a patient in need thereof the composition of claim 44.

53. An isolated polynucleotide comprising the sequence of SEQ ID NO: 11.

Patent History
Publication number: 20220220157
Type: Application
Filed: Jan 25, 2022
Publication Date: Jul 14, 2022
Applicant: GLAXOSMITHKLINE BIOLOGICALS SA (Rixensart)
Inventors: Virginia AMMENDOLA (Naples), Stefano COLLOCA (Rome), Riccardo CORTESE (Basel), Fabiana GRAZIOLI (Naples), Alfredo NICOSIA (Naples), Alessandra VITELLI (Rome)
Application Number: 17/583,511
Classifications
International Classification: C07K 14/005 (20060101); C12N 15/86 (20060101); C07K 14/075 (20060101); C07K 14/75 (20060101); A61K 39/12 (20060101); C12N 15/861 (20060101); A61K 39/155 (20060101); A61K 39/21 (20060101); C12N 7/00 (20060101);