Abstract: The present invention relates to compositions forming a low viscosity mixture of: a) at least one diacyl glycerol; b) at least one phosphatidyl choline; c) at least one oxygen containing organic solvent; d) at least one GnRH analogue; wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with an aqueous fluid. The invention further relates to methods of treatment comprising administration of such compositions, pre-filled administration devices and kits containing the formulations.

Abstract: The invention provides a composition including a succulent extract and an alginic acid component consisting of alginic acid and/or one or more salts thereof, wherein the succulent extract is present in an amount in a range from 0.1 wt % to 1000 wt % relative to the alginic acid component, both on a dry basis.

Abstract: Disclosed are compositions and methods relating to nucleic acid aptamers that specifically target CD38 protein and also selective binding to CD38-expressing cells. The ligand-drug conjugates specifically target CD38-expressing cancer cells and subsequently internalize into the cell.

Abstract: The present invention provides compositions and methods for treating acute myeloid leukemia.

Abstract: A biodegradable polyethylene glycol derivative in which a polyethylene glycol chain is linked by an acetal linker capable of accurately controlling the hydrolysis rate under different pH environments in the living body, and whose division rate into a polyethylene glycol chain of low molecular weight in the living body can be accurately controlled. The biodegradable polyethylene glycol derivative is represented by formula (1) or formula (2) as described.

Abstract: Methods and compositions are provided for treating a vascular abnormality.

Abstract: Provided is a pharmaceutical preparation composition comprising a polymerized camptothecin derivative which is obtained by bonding a camptothecin derivative to a polymer carrier, and has nanoparticle-forming properties of associating in an aqueous solution, the pharmaceutical preparation composition having enhanced preparation stability. Particularly, a pharmaceutical preparation maintaining nanoparticle-forming properties, which are an important factor, and having an excellent storage stability is provided. Disclosed is a pharmaceutical preparation comprising a block copolymer in which a polyethylene glycol segment is linked to a polyglutamic acid segment containing a glutamic acid unit having a camptothecin derivative bonded thereto, the pharmaceutical preparation capable of forming associates in an aqueous solution. When the pharmaceutical preparation is made into an aqueous solution containing the camptothecin derivative at a concentration of 1 mg/mL, the pH of the aqueous solution is 2.4 to 7.

Abstract: The present disclosure relates to conjugates, preferably, antibody-drug conjugates, directed against select non-transmembrane tumor antigens that are normally intracellular but can be secreted from cancer cells, such as human cathepsin D, and can be targeted in a way that enables the selective delivery of the conjugate to cancer cells. The design and mechanism of action disclosed enable the preferential delivery of the conjugate prodrug to cancer cells over normal cells for the purpose of selectively killing cancer cells. The uses of such conjugates for the treatment of cancer are described.

Abstract: The present invention relates to immunoconjugates for specific induction of T cell cytotoxicity against a target cell, comprising at least one T cell response eliciting peptide that is presentable via MHC class I coupled to a target cell binding moiety via a cleavable bond and methods of their production and uses thereof.

Abstract: The present invention relates to antibody- or peptide-drug conjugate compounds where one or more cryptophycin derivatives (macrocyclic depsipeptide) are covalently attached by a self-immolative linker which binds to one or more tumor-associated antigens or cell-surface receptors. The linker contains a cleavage site for proteases and a dipeptide unit able to form a diketopiperazine. These compounds may be useful in methods of diagnosis or treatment of cancer, and other diseases and disorders, such as immune or infective diseases.

Abstract: Disclosed are copolymer micelles for simultaneous delivery of Cas9 mRNA and guide RNA for Cas9 CRISPR gene editing. Also disclosed are copolymer micelles for simultaneous delivery of a therapeutic or diagnostic nucleic acid and a cross-linking or alkylating anticancer agent.

Abstract: Provided are compositions and methods for prophylaxis and/or therapy of disorders that involve seizures. The compositions and methods relate to a recombinant adeno-associated virus (rAAV) comprising a I56i enhancer sequence, and a sequence encoding hM3Dq modified muscarinic receptor (Gq-DREADD). The method includes introducing the rAAV into interneurons of an individual such that Gq-DREADD is expressed in interneurons of the individual. The method can further comprise administering to the individual an agonist of the Gq-DREADD, such for reducing or preventing seizures.

Abstract: Presented herein are methods of using encapsulated J-aggregates of indocyanine green (ICG) as a ratiometric sensor of biological activity. Upon interaction with a biological phenomenon of interest, the encapsulated J-aggregates can be released and dissolved upon rupture, inducing a detectable hypsochromic shift in the absorption spectra and corresponding increase in fluorescence. Various imaging techniques can be employed to visualize this sensor including photoacoustic imaging, two-photon imaging, fluorescence imaging, near infrared imaging, and a variety of other optical or optics-based techniques. Additionally, if the J-aggregates of ICG are also encapsulated with drugs or therapeutic molecules, the ratiometric sensing using ICG can be used to confirm drug release and delivery.

Abstract: A method of preparing a crystalline contrast agent for magnetic resonance imaging from a zwitterionic carboxylic pyridyl ligand includes mixing metal ion and the pyridyl ligand and obtaining crystals therefrom. The crystalline contrast agent includes a manganese-organic or gadolinium-organic 3D framework. The crystalline contrast agent is employed in a kit and a pharmaceutically acceptable composition. The method allows for preparing crystalline contrast agents with superior properties with easily available starting materials and with an economic and efficient process. The method allows for preparing crystalline contrast agents with exceptional water-stability and water-solubility, which exhibit high longitudinal relaxivities and with excellent stabilities under physiological conditions and low cytotoxicity. Further provided is a method for in vivo imaging of a subject, in particular a human, comprising administering the crystalline contrast agent to the subject.

Abstract: The present disclosure is generally directed to an embolic material which, in some examples, may be in the form of a microsphere or a plurality of microspheres. The embolic material may include carboxymethyl chitosan (CCN) crosslinked with partially oxidized carboxymethyl cellulose (OCMC) and an imaging agent such as at least one of an ethiodized oil, a radiopaque metal, or super paramagnetic iron oxide nanoparticles integrally contained within the microsphere.

Abstract: Provided herein are methods, compositions and kits for use in the site-specific labeling of glycoproteins comprising a combination of enzyme-mediated incorporation of modified sugars comprising a chemical handle and cycloaddition chemistry with a labeling molecule comprising a reactive group, a metal ion chelator, and/or a fluorophore.

Abstract: Systems and methods for resin cleaning are disclosed. In particular, systems and methods are provided for a resin cleaning and sterilizing system that utilizes at least two ultrasonic cleaners. A first ultrasonic cleaner provides removal of resin on a smoking apparatus, and a second ultrasonic cleaner provides sterilization of the smoking apparatus.

Abstract: Method for the decontamination and disinfection of a transport vehicle, and control device for said decontamination. The method according to the invention comprises at least one heat treatment phase of the vehicle cabin, or of at least one cabin compartment, intended for transporting, by injecting a hot gas into the same at a temperature that guarantees the elimination of the pathogens, said temperature being comprised between 0° C. and 91° C. The control device for the decontamination comprises: a control unit (1); a user interface (2); a series of conveniently distributed temperature sensors (3); and a memory (5) for the storage of data relating to dates, temperatures and other variables relating to the decontaminations carried out, as well as the identification of the vehicle on which the decontamination process is carried out.

Abstract: An assembly includes a medical package defining a housing configured to receive a medical supply. The medical package comprises a first sealable region and a second sealable region. The first and second sealable regions are configured to be sealed together to secure the medical supply within the housing. The medical package includes a thermal pattern configured to exhibit a first visible indicium indicative of an unsealed region between the first and second sealable regions. The thermal pattern is configured to irreversibly transform to a second visible indicium indicative of a sealed region between the first and second sealable regions in response to exposure to a temperature greater than or equal to a first temperature threshold, and to a third visible indicium indicative of a sterilized stage of the medical package in response to exposure to a temperature greater than or equal to a second temperature threshold.

Abstract: A liquid electrical air care device for dispensing a liquid composition from a reservoir containing the liquid composition, wherein the liquid composition includes: 0.1% to 10% by weight of the total liquid composition of a fragrance ingredient having a standard equilibrium headspace concentration (HSi) of greater than 12 to 50 micrograms/litre, and a Flexibility Index (FIi) of 45 or more; and/or 0.1% to 7% by weight of the total liquid composition of a fragrance ingredient, having a standard equilibrium headspace concentration between 5 and 12 micrograms/litre, and a Flexibility Index of between 20 and 44; and/or 0 to 1% by weight of the total liquid composition of a fragrance ingredient, having a standard equilibrium headspace concentration of less than 5 micrograms/litre, and a Flexibility Index of between 7 and 19.

Abstract: An air treating apparatus for a pet sanitary station, preferably an open, non-enclosed disposable cat litter box, and methods of liquid dosing and mounting said apparatus to an upper wall member integral or attached to the top of a vertical wall of the cat litter box. The apparatus comprises a moisture resistant, preferably paperboard blank folded approximately in-half forming a matchbook like folded apparatus having a top cover, bottom cover, opposing open sides, a convertible open and closing means, absorbent material attached to the bottom cover inside surface, three embodiments for liquid dosing the absorbent material whose fragrance or aroma permeates out said apparatus to treat the air above the cat litter and four embodiments for mounting said apparatus to the upper wall member. The invention includes methods to introduce the pet to a new fragrance, extend the useful life of used cat litter, mount, liquid dose the absorbent material, and open and close the apparatus.

Abstract: A lamp structure includes a casing, a circulation module, a power supply module, a light emitting module, an air vent, and a filter. A nano antiviral material composed of titanium dioxide and nanosilver is coated onto the filter installed at a lower end portion of the lamp structure, and the air circulation device is provided for obtaining fresh clean air after the air is filtered by the nano antiviral material and the filter, so as to achieve the effects of purifying air, deodorizing, resisting viruses and bacteria, and removing pollutants from the environment effectively for the area irradiated by the light of the lamp.

Abstract: An eye-mountable device includes a hydrogel material. By drying the hydrogel material of the eye-mountable device, ethylene oxide may be used to sterilize the eye-mountable device. Such a sterilization method can be employed to sterilize the eye-mountable device when the eye-mountable device includes electronics, sensors, actuated lenses, or other components that may be damaged by heat, pressure, radiation, or other conditions used for sterilization. The eye-mountable device may be stored, dry, within a sealed sterile volume of a packaging material. The packaging material may be permeable to ethylene oxide such that the dried eye-mountable device may be sterilized by ethylene oxide after being sealed within the packaging material. The eye-mountable device could take the form of a contact lens, the form of a device configured to be placed against a sclera of an eye beneath an eyelid of the eye, or could take some other form.

Abstract: An absorbent structure comprising a planar substrate, an auxiliary glue applied on the substrate, an absorbent material comprising from 80% to 100% by weight of superabsorbent particles deposited on the substrate on an absorbent material deposition area comprising a pattern of absorbent material land areas separated by absorbent material-free junction areas, wherein the deposition area can be notionally divided in eight deposition zones of equal length along the longitudinal direction. A fibrous thermoplastic adhesive layer immobilizes at least some of the absorbent material. The absorbent material is profiled along the longitudinal direction so that at least one of the eight deposition zones is a zone of lower absorbent material amount and the auxiliary glue is absent, or present at a level of at least 50% by weight lower than the average amount of auxiliary glue in at least one of these zones of lower absorbent material amount.

Abstract: A microporous gel system for certain applications, including biomedical applications, includes an aqueous solution containing plurality of microgel particles including a biodegradable crosslinker. In some aspects, the microgel particles act as gel building blocks that anneal to one another to form a covalently-stabilized scaffold of microgel particles having interstitial spaces therein. In certain aspects, annealing of the microgel particles occurs after exposure to an annealing agent that is endogenously present or exogenously added. In some embodiments, annealing of the microgel particles requires the presence of an initiator such as exposure to light. In particular embodiments, the chemical and physical properties of the gel building blocks can be controlled to allow downstream control of the resulting assembled scaffold. In one or more embodiments, cells are able to quickly infiltrate the interstitial spaces of the assembled scaffold.

Abstract: The present technology refers to medicine, namely hemostatic and wound healing agents, and can be used to stop bleeding of various severity, including venous, as well as to heal wounds and cuts obtained as a result of mechanical action on the epidermal and muscular layers of tissues. For this, a hemostatic agent containing an active gelling agent based on chitosan and/or its derivatives is used, characterized in that it contains chitosan, its salts and/or its derivatives in the form of a gel having a three-dimensional crosslinked structure as a polymer matrix and components of natural thrombus formation in the form of organic calcium compounds, organic acid and water coordinated on this matrix at a certain ratio of components.

Abstract: Provided is a cell culture support using a water-soluble polymer, which is a support to which cells are attached to culture the cells, and which includes: a fibrous web having a plurality of pores in which fibers containing a water-soluble polymer and a synthetic polymer obtained by electrospinning are accumulated, and into which a culture solution is penetrated, and the water-soluble polymer of the fibers gradually dissolves in the culture solution so that the cells can be grown and eluted from the fibrous web, thereby gradually reducing the diameters of the fibers.

Abstract: The disclosure provides hyaluronic acid (HA) gel formulations and methods for treating the appearance of the skin. The formulations contain hyaluronic acid and at least one additional ingredient. Methods for treating lines, wrinkles, fibroblast depletions, and scars with the disclosed composition are provided as well.

Abstract: An implant for deployment in select locations or select tissue for regeneration of tissue is disclosed. The implant includes collagen and or other bio-resorbable materials, where the implant may also be used for therapy delivery. Additionally, the implant may include, or have blended in, an additive, such as an osteoinductive factor, for example biocompatible ceramics and glass.

Abstract: An object of the present invention is to provide a porous composite that has adequate bending strength and excellent compressive strength and that contains OCP and collagen; and a bone regeneration material containing this porous composite. The present invention provides a porous composite containing octacalcium phosphate and collagen, and having a bending strength of 0.05 to 0.16 MPa and a compressive strength of 0.3 MPa or more.

Abstract: Provided is a three-dimensional printing composition including decellularized extracellular matrix; and riboflavin as a crosslinking agent. A three-dimensional structure having high mechanical strength can be prepared by performing a printing process using the three-dimensional printing composition according to the present invention and a layer-by-layer process through crosslinking under UVA light to prepare a three-dimensional structure configuration; and then performing thermal gelation of the three-dimensional structure configuration. Further provided is a method for preparing said three-dimensional printing composition and a method for preparing a three-dimensional structure using said three-dimensional printing composition.

Abstract: A biocompatible tissue graft is provided. The tissue graft includes an extracellular matrix patch and a means for reinforcing the patch.

Abstract: An anti-adhesion material comprising decellularized tissues and a biocompatible polymer or fibrin glue; a method for preparing an anti-adhesion material comprising complexing a biocompatible polymer or fibrin glue to decellularized tissues; an anti-adhesion material kit comprising decellularized tissues and a biocompatible polymer or fibrin glue; a substitute biomembrane comprising decellularized tissues and a biocompatible polymer or fibrin glue; a method for preparing a substitute biomembrane comprising complexing a biocompatible polymer or fibrin glue to decellularized tissues; and a substitute biomembrane kit comprising decellularized tissues and a biocompatible polymer or fibrin glue.

Abstract: Provided are a microneedle with excellent performance and a method for manufacturing the microneedle. A microneedle array in which a polyglycolic acid is used as a material, crystallinity of the polyglycolic acid is 21% or more and axial contraction rate of tips is 99% or more, and a manufacturing method in which a polyglycolic acid are injection-molded at a cylinder temperature of 230-280° C., a metal mold temperature of 60-130° C., and an injection pressure of 1000-1500 KPa so as to manufacture a microneedle array in which crystallinity of the polyglycolic acid is 21% or more and an axial contraction rate of tips is 99% or more.

Abstract: A chronically implanted medical device is disclosed that has an outermost layer formed from a conjugate of a polymer with lipoic acid, the conjugate having free 1,2-dithiolane groups. It is contemplated that this layer scavenges reactive oxygen species, i.e. acts as an antioxidant, and thus reduces inflammation and other adverse effects around the implant itself.

Abstract: Orthopedic and dental implants coated with an antibacterial coating and methods of making and using, are described herein. The implant can be coated with a hydrophobic, polycationic antibacterial polymer. The polymer can be covalently or non-covalently associated with the surface; however, in particular embodiments, the polymer is non-covalently associated with the surface. As shown in the examples below, clinical observations, digital radiography, and a battery of well-accepted ex vivo analytical methods show that the presence of a hydrophobic polycationic polymer coating, such as N,N-dodecyl,methyl-PEI coating on the surface of a metal implant, was effective in eliminating the clinical signs of infection in vivo in a large animal infection model. Moreover, the coated plates supported bone healing, and in fact decreased healing times, even in the presence of significant bacterial contamination compared to a control.

Abstract: A new class of rapamycin 40-O-cyclic hydrocarbon esters is disclosed. The 40-O position of the rapamycin ester has the form 40-O—R, where R is C(O)—(CH2)n—X, n is 0, 1 or 2, and X is a cyclic hydrocarbon having 3-8 carbons, optionally containing one or more unsaturated bonds, and one or more linear (CH2)n) and/or cyclic (X) carbon atoms may have an OH or halide group. Also disclosed are therapeutic compositions and methods that employ the novel analogs.

Abstract: The present invention discloses a cross-shaped double sleeve drainage tube, including an inner draining tube, a connecting member, an external sleeve tube, an inner guiding tube, a support rack, a block member, and a pressure sensor. A left end of the inner draining tube is formed in an opening, and a right end of the inner draining tube is sealed. A tube wall at the right end of the inner draining tube is provided with an inner draining hole. The connecting member combines the inner draining tube in the tunnel of the inner guiding tube. The left and right ends of the external guiding tube are formed in an opening, respectively. The tube wall at the right end of the external guiding tube is provided with a plurality of draining grooves. The inner guiding tube is installed in the tunnel of the external guiding tube through the support rack.

Abstract: A catheter device and method for treating an artery with thrombus, the catheter comprising an inflatable member. A carrier catheter has a proximal end and a distal end adapted to be inserted percutaneously into an artery, the carrier catheter having a tubular body adjacent to a rear end of the inflatable member. An inflating tube passes through the tubular body and having an open front end in fluid communication with the inflatable member to inflate same. An infusion tube is adapted to infuse pharmacologic agents, the infusion tube passing through the tubular body and having an open front end extending beyond the inflatable member. An aspiration tube is adapted to aspire the thrombus, the aspiration tube passing through the tubular body and having an open front end between the carrier catheter and the inflatable member.

Abstract: A Negative Pressure Wound Therapy (NPWT) dressing having a sealing layer on a non-wound interfacing surface. Such a sealed surface eases application and reduces the risk of a loss of seal once applied to a patient. Associated adaptors and couplers, which may be universal couplers, allow for simplified use of the disclosed and existing dressings. An optional pressure regulator unit may use existing wall suction available in medical facilities; it may interface with a transportation unit. Embodiments of the regulation unit provide for various monitoring, operation and alarming features that may be accessed using mobile wireless, wireless LAN, and internet based connectivity approaches.

Abstract: An apparatus for biomimetic expression of breast milk can comprise a breast interface having an expandable membrane configured to mimic the geometry of an infant's mouth. Various regions of the expandable membrane may be configured to simulate the structure and/or function of various parts of an infant's mouth. The expandable membrane may comprise one or more of a distal sealing region configured to simulate the lips, a superior region configured to simulate the hard palate, an inferior protruding region configured to simulate the gums, an intermediate curved region configured to simulate the tongue, and one or more internal expansion regions configured to simulate the soft palate and the throat. The expandable membrane may have a varying thickness throughout the one or more various regions to enable movement of the regions similar to the movement of the corresponding regions of an infant's mouth during nursing.

Abstract: A system for assisting a patient's heart has a pump, an oxygenator, a holder having a pump receiving portion for removably receiving the pump and an oxygenator receiving portion for removably receiving the oxygenator, and a harness configured to surround at least a portion of a patient's torso. The holder is connected to the harness. The system further has a brace connected to at least a portion of the harness. The brace is configured to extend behind a back portion of a user's head and to support tubing connected to at least one of the pump and the oxygenator. A priming tray and wet-to-wet connector connecting the cardiac assist system to the cannula are also disclosed.

Abstract: A ventricular assist device incorporating a rotary pump, such as a rotary impeller pump is implantable in fluid communication with a ventricle and an artery to assist blood flow from the ventricle to the artery. The device includes a pump drive circuit supplying power to the pump, one or more sensors for sensing one or more electrophysiological signals such as electrogram signals in and a signal processing circuit connected to the sensors and the pump drive circuit. The signal processing circuit is operative to detect the sensor signals and control power supplied to the pump from the pump drive circuit so that the pump runs in a pulsatile mode, with a varying speed synchronized with the cardiac cycle. When an arrhythmia is detected, the pump drive circuit may also run the pump in an atrial arrhythmia mode or a ventricular arrhythmia mode different from the normal pulsatile mode.

Abstract: A peritoneal dialysis system is disclosed. An example peritoneal dialysis system includes a water treatment device including a water treatment processor and a first memory and a peritoneal dialysis (“PD”) machine including a PD processor and a second memory. The PD machine is configured to mix water treated by the water treatment device with at least one concentrate to produce a peritoneal dialysis fluid for treatment. The example peritoneal dialysis system also includes a data link between the water treatment processor and the PD processor. The water treatment device is configured to prepare an amount of treated water and, upon communication between the water treatment processor and PD processor over the data link, deliver the amount of the treated water to the PD machine for use in mixing the peritoneal dialysis fluid for the treatment. The treated water has a purity corresponding to an injectable quality or a sterile quality.

Abstract: A disposable cassette and system for dialysis are disclosed. An example disposable cassette includes a rigid portion, a fluid source inlet configured to be placed in fluid communication with a fluid source, and a fluid pumping receptacle placed in fluid communication with the fluid source inlet. The fluid pumping receptacle is configured to operate with a fluid pump actuator to pump fluid from the fluid source. The example disposable cassette also includes a dampening chamber formed as part of the rigid portion and in fluid communication with the fluid pumping receptacle. The dampening chamber is sized and arranged to reduce pressure fluctuations in the fluid delivered from the fluid pumping receptacle. The example disposable cassette further includes an outlet in fluid communication with the dampening chamber. The outlet provides dialysis fluid for a dialysis treatment.

Abstract: A dialysis system is configured to enable a patient to undergo both peritoneal dialysis and extracorporeal blood treatments. The example dialysis system includes a base unit configurable to provide a first fluid for use in preforming at least one peritoneal dialysis treatment at a first time. The base unit is further configurable to provide a second, different fluid for use in at least one extracorporeal blood treatment at a second, different time. The example dialysis system also includes a blood treatment unit configured to be docked to the base unit. The blood treatment unit includes a blood pump configured to pump blood from the patient to a blood filter and from the blood filter back to the patient. The blood filter or a blood line in communication with the blood filter receives the second fluid from the base unit for use in the at least one extracorporeal blood treatment.

Abstract: High flow rate catheters, and related methods, are useful in dialysis and other procedures. A catheter according to the invention comprises a hub and a generally elongated conduit. The conduit has a substantially continuous and smooth wall. The conduit also defines at least one lumen and has a length extending from a proximal end to a distal end of the conduit. The proximal end is coupled to a hub and the distal end has an opening in communication with the lumen. The conduit has a conical shape which tapers along the length.

Abstract: Disposable fluid circuits, systems utilizing disposable fluid circuits and methods for combining a treating agent with separated blood component are disclosed. The treating agent is contained within a container and the disposable fluid circuit includes one or more frangible cannulas located in one or more flow paths of the circuit that are selectively opened to establish flow communication between the treating agent container and a treatment container, and/or a separation chamber or other container.

Abstract: The disclosure relates to devices and methods for extracorporeal conditioning of blood. Extracorporeal blood oxygenators and blood oxygenator components, such as conditioning modules, are described. An extracorporeal blood oxygenator includes a conditioning module having an external frame, an inlet cover, an outlet cover, and an internal chamber. A fiber assembly is disposed within the internal chamber and a potting material on the fiber assembly creates a circumferential seal that defines a passageway through the fiber assembly having a substantially circular cross-sectional shape. A fluid inlet is in fluid communication with the passageway, has a lumen that extends along an axis that is substantially perpendicular to the fiber assembly, and has an internal curvilinear surface adjacent the fiber assembly. A fluid outlet on the opposite side of the fiber assembly also has a lumen that extends along an axis that is substantially perpendicular to the fiber assembly.

Abstract: Methods and systems for maintaining patient fluid balance during an extracorporeal cell treatment are disclosed. The method includes minimizing the amount of saline or other fluid that is returned to the donor. Saline used during priming of the fluid circuit may be used to increase the volume of the collected cells to arrive at a treatment-ready product with a suitable hematocrit.