Therapeutic compositions and methods

Abstract

A virus (optionally having a sequence disclosed herein) capable of inhibiting the formation of methane in vivo in the human gastrointestinal tract for use in reducing the production of methane in a hu

Description

FIELD OF INVENTION The present invention relates to the reduction of methane production in humans, in particular humans suffering from irritable bowel syndrome. In particular, the invention relates to viruses capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human, for use in a method of reducing the production of methane in a human subject. The invention also relates to pharmaceutical compositions comprising a virus capable of reducing the formation of methane in vivo in the human gastrointestinal tract, and the use of these pharmaceutical compositions in methods of reducing the production of methane in humans. The invention further relates to methods of reducing the production of methane in humans, comprising administering to the human a virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract. BACKGROUND Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder affecting the human alimentary tract with a worldwide prevalence estimated at 12%. The disease affects the female population approximately twice as much as the male population and is most common in people younger than 45 years of age. Bowel movements vary considerably in their nature among IBS patients and this gives rise to categorisation into three main subtypes: diarrhoea-predominant IBS (D-IBS), constipation-predominant IBS (C-IBS), and mixed IBS (M-IBS). Faecal microbial composition differs among IBS patients depending on their stool quality and IBS categorisation. Stool firmness strongly correlates with faecal microflora diversity, there being a multispecies richness in people with firm stools which decreases across the spectrum of stool consistency reaching a minimum for diarrhoea afflicted individuals. Methanogenic archaea (commonly referred to as methanogens) are the predominant biological sources of methane in nature and Methanobrevibacter smithii is the predominant methanogen in the human intestine. These methanogens may contribute 10% of the gut microbiome and are found in the colon but also can be demonstrated to reside in the small bowel, especially when small intestine bacterial overgrowth exists. An increased abundance of these methanogens is found in harder stools of C-IBS patients compared with diarrhoea of D-IBS patients and elevated production of methane is associated with constipation. Indeed, methane is a putative neurotransmitter acting on the cholinergic pathway of the enteric nervous system causing delayed intestinal transit time of ingesta and promoting segmental (non-propagating) peristaltic contractions. IBS is an important health care concern as it greatly affects patients’ quality of life. In particular, C-IBS may negatively impact general wellbeing through abdominal pain, bloating and altered bowel habits. Given that C-IBS patients experience increased methane production due to an increased abundance of methanogens, a reduction of methanogenesis in these patients is one therapeutic strategy to achieve symptomatic relief. Previously, this has been performed using pharmaceuticals such as the prodrug lactone form of lovastatin, or by antibiotics such as rifaximin and neomycin. However, these drugs have drawbacks in that they disrupt the enteric microbiome through indiscriminate effects. Thus, there is a need for more targeted strategies for reducing the production of methane in patients suffering from IBS, particularly those with C-IBS, because elevated production of methane is associated with adverse symptoms including discomfort due to bloating, and constipation, so a reduction in methane production in these patients would improve their quality of life. The present invention addresses this need. WO2024 / 013394 has a priority date before the priority date of the present application and a publication date after the priority date of the present application. It discloses solid and semisolid compositions for administration to a ruminant which comprise a substance capable of inhibiting the production of methane in vivo in the ruminant, such as a virus capable of inhibiting archaea that produce methane in vivo in a ruminant. Such compositions are disclaimed herein. SUMMARY OF INVENTION In a first aspect of the invention, there is provided a virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human for use in a method of reducing the production of methane in a human subject, the method comprising administering the virus to the subject. In a second aspect of the invention, there is provided a pharmaceutical composition comprising a virus capable of inhibiting the formation of methane in vivo in the human gastrointestinal tract. The pharmaceutical composition according to this aspect may be for use in a method of reducing the production of methane in a human subject, the method comprising administering the composition to the subject. In a third aspect of the invention, there is provided a method of reducing the production of methane in a human subject, comprising administering to the subject a virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract. The inventive viruses for use, pharmaceutical compositions and methods provide an effective means to reduce methane production in humans, particularly in patients with C-IBS who exhibit elevated levels of methane production. The reduction of methane production in these patients reduces symptoms associated with C-IBS, including constipation. DEFINITIONS The term “comprising”, “including” and “includes” as used herein means that at least all of the listed elements must be present, but other elements that are not mentioned may also be present. The term “consisting of” as used herein means that only the listed elements must be present, such that other elements that are not mentioned are not present. The terms “constipation-predominant irritable bowel syndrome” and “C-IBS” as used interchangeably herein define the subtype of irritable bowel syndrome which is defined as abdominal pain with hard or lumpy stools characterising more than 25% of bowel movements and loose or watery stools constituting less than 25% of bowel movements for an average of three days per month over a span of last three months using the Rome IV criteria for irritable bowel syndrome. The term "virus" according to the present invention includes double-stranded or singlestranded RNA or DNA viruses, which infect cells of bacteria, archaea, plants and / or animals. The term “archaea” as used herein refers to any single-celled prokaryotic organism. The term "substrate" according to the present invention is understood to mean any solid phase material to which a virus may be immobilised. The terms “virus capable of inhibiting the production of methane” and “virus” are used interchangeably herein to refer to a virus capable of inhibiting the production of methane in vivo in a human. As used herein, the term “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In some embodiments, the term “about” refers to a range of values that fall within 25% of the reference value in either direction (greater than or less than the reference value). In some embodiments, the term “about” refers to values that fall within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the stated reference value (except where such number would exceed 100% of a possible value). The term “coated” as used herein with respect to a particular pharmaceutical composition refers to the presence of a coating on at least 10% of the external surface of the pharmaceutical composition. In some embodiments, the coating is present on at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of the external surface. The term “encapsulated” as used herein with respect to coating of pharmaceutical compositions means that the pharmaceutical composition is enclosed within the coating (in other words, the pharmaceutical composition is contained entirely within the coating). As used herein, “location-controlled release” means that the virus is released at a particular location within the human digestive tract after it is administered. DETAILED DESCRIPTION The present invention relates to a virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human, for use in a method of reducing the production of methane in a human. The present invention further relates to a pharmaceutical composition comprising a virus capable of reducing the formation of methane in vivo in the human gastrointestinal tract. The pharmaceutical composition may be in the form of a liquid, syrup, capsule, tablet, bead, granule, pellet, lozenge, suppository or pill, preferably a tablet. Even more preferably, the pharmaceutical composition may be in the form of tablet which is coated with an enteric coating. The pharmaceutical composition may be for use in a method of reducing the production of methane in a human subject, the method comprising administering the composition to the subject. The pharmaceutical composition preferably also comprises a pharmaceutically acceptable carrier. The present invention also relates to methods for reducing methane production in a human subject, comprising administering to the subject a virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract. In preferred embodiments, the human has IBS. In particularly preferred embodiments, the human has C-IBS. This is advantageous because methane production is particularly elevated in patients with C-IBS, causing adverse effects such as constipation. Thus, the reduction of methane production in these patients alleviates these adverse effects. The administration of the virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract is preferably oral administration or rectal administration, most preferably oral administration. In this way, the virus is directly introduced into the gastrointestinal tract and can reduce methane production there. The virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract may be a virus which interrupts the metabolic pathway of methane production in the gastrointestinal tract, and / or may be a virus capable of disrupting the enteric microbiome. In preferred embodiments, the virus is an inhibitor of methanogens. In particularly preferred embodiments, the virus is an inhibitor of methanogens in the Methanobrevibacter genus. In particularly preferred embodiments, the virus is an inhibitor of Methanobrevibacter smithii. These viruses are particularly effective in reducing methane production in humans because Methanobrevibacter smithii is the predominant enteric methanogen, so administration of a virus which inhibits it will be particularly effective in reducing methane production in a human. In preferred embodiments, the virus capable of inhibiting methane production in vivo in a human is a stabilised virus. For example, the virus is stabilised as described in EP 1496919 B1, by immobilisation to a substrate. This is advantageous because it ensures that the virus retains its ability to inhibit the production of methane while also improving its stability relative to a free virus. In some embodiments, as described in EP 1496919 B1, the virus is immobilised to the substrate via covalent bonds formed between the substrate and the virus. In preferred embodiments, the virus is immobilised via its head, leaving the tail free. This ensures that the virus retains its activity, because the tail of the virus is involved in its ability to recognise and infect specific bacteria and / or archaea. In some embodiments, the virus may be a bacteriophage. Advantageously, given that methane production in the gastrointestinal tract is caused by specific prokaryotic methanogens, the use of viruses offers a particularly effective means to provide targeted disruption of the methane production process. Unlike other methane- inhibiting agents, which provide a less targeted approach and can cause toxicity to the human, viruses are specific to their target bacteria and / or archaea and thus do not have problematic side effects for the human. Thus, they provide an effective and targeted means for reducing methane production in humans and offer a promising method for alleviating symptoms associated with elevated methane production, such as those suffered by patients with C-IBS. In a preferred embodiment, the virus is a bacteriophage which targets bacteria in the enteric microbiome. This is advantageous because the inhibition of these bacteria will, by extension, negatively impact the production of methane in the gastrointestinal tract. In another preferred embodiment, the virus is a virus which targets archaea which are involved in the production of methane in the gastrointestinal tract of humans. In a particularly preferred embodiment, the virus is a virus which targets metabolic processes leading methanogenesis. It will be appreciated that viruses capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human can be isolated by the skilled person. For example, to isolate a virus which targets archaea, archaea cultures can be prepared in suitable growth media such as 119 Broth. Then, liquid can be harvested from a suitable source of viruses, for example, bovine rumen fluid, rumen faecal material, municipal sewage systems, or environmental samples from sources that provide habitats for Archaea, such as anaerobic soils including peat and peat bogs, thermal springs deep ocean thermal vents. Viruses can then be separated from the liquid, concentrated, and purified, for example by PEG precipitation and ultracentrifugation. The archaea cultures can then be inoculated with the resulting virus suspension and the cultures allowed to grow to allow viruses with specificity for the archaea to initiate a cycle of infection and amplification. These viruses can be filtered from the cultures and passaged repeatedly (i.e., repeating the previous steps with fresh archaea) to obtain pure active viruses. Similar procedures can be followed to isolate other viruses. Following a procedure as described above, a novel virus with activity against Methanobrevibacter smithii was isolated, which had a sequence as set forth in SEQ ID NO:1. The isolation method is described in more detail in the Examples and in WO2024 / 013394 A1, which is incorporated by reference in its entirety. In some embodiments, the nucleic acid of the capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human comprises at least 50% identity to SEQ ID NO:1. In some embodiments, the nucleic acid of the virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human comprises at least 60% identity to SEQ ID NO:1. In some embodiments, the nucleic acid of the virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human comprises at least 70% identity to SEQ ID NO:1. In some embodiments, the nucleic acid of the virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human comprises at least 80% identity to SEQ ID NO:1. In some embodiments, the virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human has a nucleic acid comprising at least 90% identity to SEQ ID NO:1. In some embodiments, the virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human has a nucleic acid comprising at least 95% identity to SEQ ID NO:1. In particularly preferred embodiments, the virus has a sequence as set forth in SEQ ID NO:1. SEQ ID NO:1: GTCCTGGTGTTTCTCCAAGGTCTACTTTTATGCTTTCATTTTTCTCTAACCATTTTGTGT TATCTCCCGAACCGTTTAATTTTTGCCAGCACCCAATCAATACTTCTTCTACTGATTGTT C GCTAGT T T CAAAT GGT T CTAAT T T T GGAT TAGAAT CACATAC T GT GAGATAAT T GAAAT CTACAAGTGTTGGTAAAGCATGAATATATAATTCTCCTCTTGGTTTTACATAGGGGAATC T T GAAAAT T CAAAAAGT T T T GT T GTAT CACAT GT TAAT GATACAAAAT CACAT CC T T T TA GTTTGAAAGTTACGTTGCCGTACCAGTAGTTGAATTTTGATTGTTTTGTGATTACATTTA CTATATTTTGTTTTGAATCACTTTCATCACCAGTATATTCTGCAGTTATTTCTTTATATT CTCCTACTTTTTCTTTGACTGTTTTTGTTGCAGTGGTTGTTGTTTCTGCTTCTCCAGGAG TTAATTTAACTTTTTTACATTTACCATGACCCCATTTGTCTCCTCCACAGTATCCGCAGT AATCTGCGTCACATCCTCCTTTTTTCATGCTGCAAGTTATTTCGCCTTCGTACACTTTTT TAGGATTGTCGGTTAATGTTCCAGTTTTGCCACAGTTTGGGCAGTAGTTTTTCCAGGTTT TTGTGTATCTTTTATATGCTGTTCCTGCACAACAGCCACATGATGGCATCATGTTTACGG TTATTGTGTTGGGATCTCCTGTTGTGACATTTTCAGTTACCTGTTTTTCTACTTCTTTTT CAACATAT T T CAT GAAT T T TAT T GAC T TAT T T T T GTAGT CAATAGT TAT T T C GCT T T CAT CCTGAATTAGATTCGGTTGTTGGAAATATATCATTGAAGTATTGGGATCATCATCTGCTA TTCCCTGATTAGTTATTTCAATTCCTAGTGTGGATGCTCCTTTTATTTTTTTAATTTTGA GAATAGGGTATGATTCGCTGATATATTTTTCAACATCTAAAATAGTACATCCTGGGATTT GAC GT GGT GTAAT GGT T GGGAT T T TAT T T GAAGAGGT T GTAT T T T GT GT GTACAT GAAT G GCATGTATTCGTAGTTTTCATAATCTTTTATATAGTGAATATTTTCTTGTACAAATGTTA AAGAAACAGT GT C TAT TAT T T T TAGT T CAT TAGAAT TAAAGAAAACAT CT T TTTTTGTTG TTAAATATTTTGCAAGAACATATATCAAATATTGGAAGCTTAGTCTTCCACCTGTAATTG ATAAGCTGTTTGGTGCTTTTGTTTGAGTTATGCAGTACGATTTGATTATTCTTGCTAATT GT AT TAT T T CAT C CT GT T T T AT GAT GC AGT C AAT AT GGC T GT GT GAT GGT AAAT C T GC AC AATCTACAATTTTAAGTGAAATGTTTTCAGAGTTATTGTCTTCAGTGTTGATTATTGCTT CTGCAAGTAGAAGTATCATTTGTCCCATGCCTATTTTAACATTGTAGACTTTGTTTTTTG ATGAATCTTCATATATTTCACTATGTGATATTTCAAACTTGTTTGGGAAGTATTTTTGAA CAT CAAGAAGTAC TAATAGT T T T T CAGCACAAT CAATAAT GT C T T GTAT GTAAAAAT CAT AT T CAAATAAT GT T GGT GGAATAT TAT T GT T TAG GT CAAGAT T GTAAAAT T GT CTAAGTA TTTTTGAATAATCTACTTCATCAGTATTTTCTGAAGAAATTACTGGCATTATACCTAATG CATTTTTGGTTTCATCACTACTATATGATAATTCATTAGTATTTTCTCCAATTACAACAC TTTCTACAATTTTATTGTGTGTTACTCCATAATTTGCAGGTTTTAGTAATTGTATTTCTT TTATAATGTTATTATTTTTTAAAGAATAATTTGTTTTAAATACTAATCCTGATTGTTTTT CAATAGCTTTTAATAAGTTGTATTTTGTTATTGAGCCTTGAACATTGATTAATCTTTTAC TATAATCAATACT GTCAATATCT GTT TTT GTAACATT GAAAAATCCT TTCAGTAATTT GT TTAGGAATAATTTACTGATAATGATTGTATTTCCATTTACATGTGAAGCATAATTGGGAT CTCGGATATAGAATGGTTTACAATTGTTTAATTCTACAATTATTTCTTCTGCATCTACAT CAATAGAT T T GT C TATATAAT CAAAGGT GCAT T CACTAT TAATAACAAACAAACAAT TAT CAACAAAGATTTTGTTTCCTTGTTTGAATAATTGCTTGTCTCTTTTAACATTTGTAAGTT TATGTGATAGTTTTAATGTTTCATATCCTTGATATTCATCAGTAATATGTATTTCTGATA ATTCAGTATCTAAAAATTGAAGAATATTTTCTTGATTATCTAAAACAACAACCATACTTT TTATCCTCCTTTTTCATAGTAAATTACATCAGTCACTTTACAATTGATACTGTTTTCAAA ATTAAAATGATGATCCAATATGAAAAAACTAGAATCTACACTAATACAATTAGGATCTAT CTTGAACCATTCACTATATTTTTCATAGAATACATTTCTATTTTCACAATCAATTTTAAT CTTTGTTGTTTCAGGTAAGTTTGTTATAAACTCTCCTTCAAGTTTCATTAGTTGTCCAGA TTCTGATTCAATTATTTGTATGCTTGTTGATTCATCTTCACTTAATTTATACAAAATAAT GTCTGGTTTTACTTTTCCAATTGTGGTTATTGTTCCTGCGAAACTTTTTCTTAATGGGTT AATATTTCTACTTAAACCACTAGGGATTATTAAGTTCACTTCACAATCATAACCTCCAAC CATTGCTTCTGCATCAATTGAATCTTCTATATAGTAATCAAAACATTCTTCAGGTGCGAA AAAGAAACTAATACTTTTTAGAATTGGTGAATCTAATGTGTCTCTTTCAGGATACAGGTA GTCACTTACATATTTCATGATTTCTGTTGATTCTTCAAAATCATCTCCGTAAACTCTGAA TTTTAATTTGATTTTTTTATCATCAACATTGACTCTTATAGGGTATTTCCCATCTGCTCC TTCAATTTTATATTTTTCTGTATCAAAATTAGCTCCACGAGGTATTTCTGTTTCAGGACT CATACTTATAAGGAAATATTTGCAACTAACACCATTAATATAGAAATCGCAGTCTTCTCC ACTATTTTTTGAATAATATACTGTGATTTGCACATTTTTCATTTCGACTTGGACTTGAGT GACAT T GT CAAAT GCAT CAT CAAT T T GTAAGAAAAACCT TAAAT CAT T TAATAT T GT GT T GATTTCTGGAAATGGAATGCCGAAATTATGGAATTTTCCACCGAATTTAAAGTTAGTGTC ATTTCTAGTGATGTTTATGCTGTCTAAATAGTAATCTAATTCATCATCATCTAATGTTCC AACACCACAAATTAGATTAATTGATTCTTCAACACTTATGTCTCCAGTTATTTCTATTCC AT GAAT CAGTACAT TAT T GT T T T CTAAT CC T T GC CAGT T GAAACCT T CAAAGAAAT GT T T TGTAGATAAAGCTAACTCTGGAGGTTCAAGTAATAAATTTGCAGTGCTGCCTACATCACC TAACAAATATCTTTTTGGAGATAAAGCCAATACTGGATATTCATAACCTGCATATCTTTC T T TAAGTAT TAAAGATAAAT TACCAAAT T C TAGAGT T CCATAGT CAAAAT C TAT GAAAT T CCCATAAAAAATTAGATAGATTGGTTTACTTGCATCATATGTAAACTCACAGGATAACTC TTCCCATATGTCCTTAACACTGATTTGATTGGTGTATGAATTTGTTGTTCCATTTACAAC ACAAACTCTTAAGTTTTTCAAACCTTTTTCAATTTTAGAAGCATTTAACAGTCTTCCTAA T GCT GAGAAAACATAAGTTTCACCAT GTTCAAGGTTT GATAAT GT GAATTCT GATAAATT CAATATTGAATAATAGGATTTATATGAATCAGGAATGTTTACTTTCACTTTATCTGTGAA AACACCTAATAATAATGGACTGGTCATTTCAATATTATGCTCTCCACTACTTTTAGAGTA TAAAGGAATATTTGTATCAAAAACAATGTTTCCACTATCATCTTTTTGCCATTGTGATTT TGAAATTTGTAAAATATTATTTGATAATCCTGGAACAGGTTCTTTTACAGTTAATCCTCC AAAATTCAGATTTAGTGTTAAATCTAATGGAGCATCAGTTTTTAAAGTTATGTTTAAGTA TGTTAAATCTGTAACTGTATCTGTACTAATTTCAATTTCTTTGTTATTTGCATAGAAATC CCATACTTCCAATTGGGGTTTTTCTACTACAAATGTTGTTTTTGTTGAATGGCCACTATT GT T T T CAT CAAGT GT GAT T GTAAACAAT CC T T CAGAT GT T GGAGT TACATAGAATAT TAA TTCTGCTTTACCATTTGTTGTTGCTTGTCTCCATATGCCTGTGGTCCAGTCATAATATGG TGAATCATATGTGATTTCACAGTCTCCATTTGTGATTATCTTTATGTTTGCCGATATTTC TTCTGAAGGTTTTGTTCCACTGGTTTCAACCATTGTGCATTTTACAGCTACTTTTTCACC GTAACTAACAATATTTGGTTCAATGCTAATGCTTGGAATATAATTTCCAGTTGTATACAC TACAATTACTCTTAAGTATTTCATTTCAATGTAACATGGGTTTGTAGATGTATTTTGTGG TAAATCAAATTTAACATCAAAATTTGGAGTGTTAATGTCTTTTCCTTTTAGATTCAAATT ATTAAATTGAACTTCATATTCTCCAAAATTATTTCTAGGTGGGGCATTACCTGTTTTTGA CAGGTTTAAACTACTTAATATGATTTCTGGATTTGAAAAACTTCCATGTGCAGTTTGACT TATCTGTGCAGAGTATGCTAATTTTCTATATGAATATTGTACTATTATACTCGTTACTTT AGCTGAATCTGGAATTAATCCATCATATTTAAAATCATATCCACGTATGGTTGATGGATG TTTTCTTGAACCATTTCTTCCAGCAATCGCATTTTTATATTTTGCTCCAGGATCTGCATA ACCCCAATGTCCCACAGTATTTAAATCATTTGTAATATTTTCAATATGATCACATGAACG ATAAGGTATGTTGTTTCCTTCTATATTTTGAACTTTACTAGGATATCTTAAAATACTAGG CAATTTAATAATCCCTCCATCATTTTTTTTAATTTTTAATAAAACCATCATACTCTGAAT TAAACAATAAACAGTTTAATTGAAAGCTAATGTAATCTCCTTTACTTACCCCATCAGGAA AAGCAAATTCAACACTCACATATTTAGCACCAGCAGGTATTTTTGATGTTTTAATAGCAC ATCTTCCTTTATTACCCATACCTTCATTAGCAATATCCATAATTTCCTGATTTTCAATTA ATTTACCATCTTTATCGAAAAATACAAACCCAACAAGTATGCTTTCAATAGTGTTTTTTG CAT CATAAT TAGAT GAAAACACAATACT GGAAGCAT CAT CAGGTAT GTGTACTCCTT GAT T GT T CT GAT GGAT TAAAAGAAAAAAAGGAGAAGT TAAAT CAACAT T C T CC GAGAGATAT G T T T C T T TAACT T T CAAAGTATAACCAT T T C TAAAAGGAACAAC T T CAAAAAAAT CACTAT AT GG GT T GAAAT T AAAAT CAAAAT GT T CACAAACAAACAAAC T AGAT AAAC TAGAT T C CA TACAATATTGAATATCTTCACTAAATCTGTTAGTTAATGAAACATCTTTACTTAATTTAA AT GAATATACAT T GTAAGAT T C CCAT T CAT CAGGT T T TAGAT TAT T TAAT GAAAC CATAC AT T TAT GT GAT T CAAAAT C GT T T T TAT CT T CCAGATAT C CAT GTTTGTTACTTAT GATAT TACCGAAGATTTCACATTCTTCAGGATTAATTTTTATAGTTTCCATTATCTTTTAACCTC TCATTCTTTTAATACGATTGTCTCTTTTAATTAAAGCTTCAGCAATGCGGTCAATTAATT TGGAATCAGTTATCACTTCTTTTAAAGTTGTGATTATTGATTTTTCATCAATATCTTCTC CT T CAACAGTAACAT TAAGAT TAT GAT CTAT T GT TAAAT GCACAT CAT CAGAT GTATAAG ACAC TAAAT TAT CAGCAGTAGTAT TAT T CC TAT TAT GT T CAATAT T C T GGAAGTAT GCAT T T T GAT T T GT T T T CAT TAAAT CAATAATAT TATATAT T C CAT C T GTAAT GAT T CC GAATA CATCTTTAGAACTTCCTCCAGGACTTGCTGAACCAAAACTAACTCCAGAACCTCCGCGGA ATATTCCTCCACGTTTTTGGAATTGTGTCATATCATATATTTGACCATTAACCATAGCTG CTACATGGCCTATTCCATTCCATGATCCATGAATCATGTGTCCTGATAATCCCAACATAG ATGCTATTTCAATTATCATTTCTGCACCATCAAAACAGTTGCATCTTACTTGATCCCAAA CTTGCTGATTACTATATCTTGAATTATAATAAAATTCATAAGTTCCAGGGTTTTGGAATC CTCTTGCAGTTAAGATTTTTCTTAGAAGATTTTCAAAGTTTCCAGGATTTAATTGCGGTT GTTTTCCATCACGGAAATCTTCCACATGATAATCTGAAGGTATTTGAATTCCAAGGAACC ATGGGTCTGCTATCCTCCATTTGTATGCAGTATTCATTATTTTATTCACATTAGTATCAG GAATTCCTGCAAAACAAGTATTTGGATTAACACAACCATTAACTCTTGCCAAATCATTAA TTACGCTTGTTGGTAAATTATAATCTAAAAGATTTAACCATGATTTGCTTTTATTGTTTT GAGGATGTTTTACTTTAGAATTAGTGTCAATTACTCTGCCTTTTCCTTGTCCTAATCCTC CAGCAGCATAACTTGCTATTGTGCCTTTTGTGGATTTTCCAAAGTTAATGCTTCCACCAG GTAATGTTCTGCCTCCAATTAATCCTCTTGTTGAATTAGTTGCTGGGCCTGCAGGCAGTC CACTACT GAAAT GT GCAT T GGC TAAT T GAT TATAGAAAC T T GCAATACT T C TAT GAAGGC TGCTGAATTTATTGTATGATTGTGTTTGTATGCTTCCTGCAGCTGAAACAATATTGTCTT TCATTACTCCCCATGCATTAGTCATTTTATTTGTTACATCTATTGTGGAGTTACGTACTT GAT T TAAGT T CT GGGT T GT T GT T GAT T TAATAT T GT T CCAT GC T T GAGTAT T T GAAT TAG TCATGCTTGTTAATGCAGTGGTTACTCCATTACGTGTTGTTTGGAAGCTTGTTACTACTC CTGCAACTCTCATTTGAATAGCTCCTGCATTTAATGCTATTCCTGCAGTTAATGTTGAAA AGCTTGTTCCGATCATATTGTTGCTTGCAGTGATGCTTTCACTAGCTAATGATACTTCTT CAACAAGACCATTATATTGGTCTCCAGTTTCTTCTGTACCTGAATTATTATTGCTTAAAT CAACATTTGCACTATCTGTTTCAACTTCAGTGTTTGTTGTTACTGGAGTTGTGATAGTTG T T GAAATAT TAT T TAAT GCAT T T T CAACAT CAGCAGTAT T GAAT CCAT T TAGAAT GT T T T TTCCAACATTTTTACCTGCTTCATATGCTGATTTTCCTTTGTCTTTAACTCTTTGTAGCA TGTTAAAGAATTCTAGTACTACTTTTTCTTGGATTATTCCTGGTGAATGTATTCCCATTG CGGAAAGCATTCCGTCTACAATTTTTTTACCGATTTGCTTTGCATTTTCAACTAATTGTG AACCTGCAGATAGTATTCTTGAGCCTATGTTTAGGAATTCCTGGTATACTTTTTGAGGTA ATTGCTTTATCCAGGACATTACTCCAGATACTACTTGTGATGCTTTTGTTTTAGCATTAC TTACCCATTGTGCTCCTGCAGTTATTACTCTTACAGCAACTGCTAAAAGATACATTTTTA TTTTATCTGGCAATTGTCGGATAAATTGAACTACTCCTGTAAGGAAGTTTCTACCAGTAT TAACTGCATTATTCCACATTGACTGAGCCCAACTAACAACACGATTAATCACATTTGATA ATATTGTGCTGATTGTTGATTGAATAGCTGCCCAAGCCCAAGCAATTGCTTGTTGAAGAC TTATTTGACCAGTAATTAACTGGCTAAAAATTGTTGCCAGTTGCATGAATAAATTGAATA AT GGAGT TACAATAT CAAGTACAAGT T GCCAT GC T GGAC CAAATACACT TAATAAGAAT G AT GCAAT T C CAT T GAAAACAT C CCATAT TAT GGT GAGTAT GT C TAT T GCAAGT T GAACT C TAACTTTGAAACTTTCAAATACTGCTCCTATTGCATCGATAACTGCTCTTGTTCCATCAA CTTTACCTTTTGCACTTTCTGGGAATATTTCATCCCATATTCCTTTCAACCAATCTACAA CTGGTTTGAGAGATTCATTCAAATCAGACCATGCATCTTGAATTGCTTTGATAGTTGCTT TTACATCAGGATGATTTATGAATGCATCCCATAATCTACCAATATTATTCTTTATGGCTT CGAGCATGGTTCCTACATCTTTCCACCAACCAAAAGCTTTACCTACTTCATATATTGCTA CTGCTATTGCAACTAATGCCACAACAACCCATGTTAATGGATTTGATAAAATTGCTCCTG CAACTGCTAAAAAACTAGCCGCCAAACCCATATTTGCTATTTCAACACCTAATGCTCCAG CAATATAAGTTACAAAACTAGTCGCACTAGCAGCTATTGCGGGAATTACTGAACCAAGAA TTACAATACCCAACCCAACTAAAGCTGTTGAAAGTACACCAATAGTTACTGCTGCTTTAG CCCAATCGGGCATGCTTGACCATGCTGATTGTAATGCTTCAACCATCCAAGTAATCATTT CAACAACTGTTATAATTATGGGAGTTATTGGGACAAGGATAGATTGTATTAATTTGCTTC CAGTTACTGTTAATGCTGCCCAAGCATCATCTAATGTTACAATTTCTTGTGCGGACTGTT CAAAACCCATATCGCTAAGTGTTTTGTTCATTGCTTGGAGTAATCCAGTTTTATTATTTA TATCTCCATCCCATCCATTTTTCATGAGCATGTCTTGAGATATGCCTATTTCCTGCAGTC TTCTGAATTGGCCATCCATTGCATCTGATACTGCAAGTATTGCATCTTCTTGTGTTCTTC CTTCTTTTACGAAAGCTGAACTCATTACTGCAGTTGTTTTAGTAAGTTCATCCATTGAAG CTTTAGGAAGTTTTAATTTCACTCCCATTTCTAATGCGGCTGCACCTACTGCATTCATAT CTACTTTTCTGAAGCTATCTTGCATTTTGTCAACAGCCCCATGGAATTGTTGTAGTTCTC CTTCAGTCATTCCTAATCTTTGACCGAATCTTTCAAAACTTGCAGCTGCATTTATTGATT CTCTTGCTCCTTGAACCATACTGTTTACAAGGTCAAAACCAATCATTCCTACAGTCATAC TTGCTGCTGTTCTAAGAAATCCAAGACCTCCACCTGCAGTTTTAGCTCCGTTTTCAAGTC CTCCGAAACCAGTTCCTGTTTTTTGTGAACTTGTTCTTAAACCTTCTAAAGCTAATTGTG CTTCTCTTGCATCTCTTGTAACATTATCTAAACCAGTAGTATGGAAGTTTAGCAATGAAT TTACTTGTTGAAGTATACCAATTAAAACTAATAATATTGCTTTTAGTAGTTCTGCTGATG CTGTTGTTCTACTGAATCCCGAACCATCAATTGAATCTAAGGCTGCATCTGTTGAATGTG CACTTGTTCTAGCTCGATCTAATGCCATGTCTAATTGTGCTGCACTTGATGAAGTTGCTG TTAATGTGTATCCAGTTATACTATTTATTCCACTGCTTAAACTAAGTGCACTGGATGAAG CTTGTTTTAAACTTGAAGATAATAATCTGGTACTATTATTTGAACTATTCATCGAGGAAG ATAATCTTGTAGCACTAGATGATGCTGTGAGTAAATTACCTGAATTAATTGTGTTGATTG AAGTGTTAAGTCTATATGCACTATTCATCGATGTATCCATTGAAGTGGTTAATAGTTTTG CAGAAT TAGATAAT T GAT TAAT T GTAT T GGGAT T GAT T GAAT T TAAT GCT GT T T T T GTAG AATTAGTGCGATTTGTAACTTCAGTTAATTCTTTATCTAACTGATTAGCAGAGTTTTTGG CTTTATCCATACTTGAGGAATCAAATTGTCGCATTGCATTTTGAGCTTGTTGTGCTGCTT TTTGAACTTGCTCCATTTGTGCTTGTATCTCTTTTAATTGAGCTTTAACACGGTTTTCCA GTTCAATTATTAACTTTACAATATTATTGCTCATTATTCTATTCCTCTGCTAATTTCTTG TTTTTTTCTTCTGACACGGTCTTTTAGAGAATGTGAAGCATGATTTGTACCTGAAGATTG TTTATCCTGTTTATCACGAACTAAGGGTACTGCATGATTCAAGAATAATTTCTGCCTAAT AGTTAAATCTGCTTGGTTTTCTGCTAACATATAACCGATGTCTTGAAGAGTTACTACTTC AATAGCTATGTTTTCATTCTTCTTCACGAAATTCTGCTATATTATTATCCATTGATTTAA GGTTATCTAAACCACTGAAAATTAATGCTTCATTTACAATTAAGTCTAATGTTCCTGCTT TTAATTGTTCAAGGTCTTTTTTGGTGAATTTATCAGGATTGTCTGCATTGTCTAATACTT TTAATGCAAGGTTCATTTTTGCATCATATTTCTTTTTTTCCATTGCTGCGAGACTGGTTT TGAATTTTGTGGTGTCTTCTGCAAGGCTGGTTTGTTTTGCTTTGATGGTGGAAATCATGT CGAAGTTTCCTACATCACGGTATGCTGATGTGAATTGGTTGTATTCAAGGTCGCTTATTT CTCTTATTGCTACTTCATTATCGTACATTGGTAGTTCGATTATTTTTGTGTTTTTGATTC CGCCGATGATCATTTCTTTTGTAAGCATAAATATCACATTTTTATATAATAATTTTTTTT T GAAT T T TAAATAAAGTAAT T GAAT GAGAATAAT CATAT T CT CAT T T CAT T TAAT CT GT G TAAACAGTGATTGTTTTTGTTTTACTTGCACCATCAATTAAAATATGTGCTGGTTCTACT TTAGTTGCAGTTGGTTCACCAGTCAACTCTATATCATACACTCCATCTTCAGCAGTAAGT GT TACT T CACCAT TACT T GAAGAT T CAGCAT CAACAGT T GT GGAT CC T T T CAT TAAT GAT ACTGTGTAATCAGTTGTTAATTTAGCACCTTCCTTATCAACAAGTTTTATTGTTGCATCA TAAGTTGGGTTGGGATCACTGTCTGCTTTTCTTGCAAATAATGCTCCAGCTAAATTTTTA TAAT GGTCCATTGTT GAT T CAACT GT T T T T GATAAACAAACAATACT TAAT T CATAT T TA ACT GGGTCT GCAT TCAT T GTT GCAGAT GGT T GGT T GATAATACACAT T GGACAATATAAT T C GAAT T T T T TAT CACCAT T T C TAAT GTAGAACAT TAAT T CAAAGTAT T CT CCT GCAAGG TATCTTCTTGGTCCTTCCTCACTTCCCCAGTACATTTCCAAGTATTTTTCATCAGTATCA TCTACTGTTAAGTTTAAACCAATTTCTCTTTTAGCTGCTCTTGGTATTTTACACATAAAC CTTGAGCCCATTCCTCTTGCATCATCAGTATTAACATTGTTTTTGATTTCAAGACTTATT TTATTGGTTTTACATCTCATTTCAGTCCATTCATCTTCACCAAATCTTCTCATTTTAACA CTGTCTATATGGTAAAATGATAATGGTAATTTTCCAAAGTTAAACTCTGATAATTTTTTT AATGGTTGTTTACTATTGATTTTTGATTTGATTTCTGCTGATGCAGTTAAGAATTCTGAT TCTACTTCAATACTTAAACTGTCCATCACCATACCTAAAATTTCCATCTCGTAGGTTGCA CATCCTGCCATCACAGTATAAGAAGGTAAGATACTACTATTTGTACCGTAGATAATATCT CCTTCTCTTCTTCCCAATACTGCTTCAAGAAGGTATTCTAATGTTTCCATTTGTAAGTTG CAACTGAAACTGTTTTCAGGTACATAGTAAGCAGCTACACCAGATTGATAATCCCTACTT ACTACTGAATCATATTTTGTAAATTGCTCTGGTGGAGATACATCCATCTCTGATATTTCA ATATCAATAGATTCTCCACTAAGGTCTTTTTTTGCAAATTCTCCTTCTTTTACTAATCTT AAATATTTTAGTTCTTCTGCGGCTGTTACCATATTCTTTAGCCTCCATCACATTTTGAAT TCTTAATTTTAAATCTTATTTGGAATGTTACACCTGCACTATACACATTTTTCTTTTTAC CCAGACCATATGGAACCCATCCGAAATCCTTGGTTTTAATATTGAAAAATTCTAAGTCTC CAAGTAATCTTGAACTTATTATTCTACGTTCTGCCTGTGAAACTATACTTGTAGCTTCAT GAATACCTATCTTAGGATTTTTATTGTTAAGCACCTGTGAGGATAATATTATTTCTCCTT CAAAGGTTTCACTTAAACCAGTATCAGTAATATTTTTAAATGGTTCATCTACCCATAATT CCAGATAAGGTAATTCTGGTGTTCCCAGACTTACACCCATAAGAGATAAATGTTTAATAG TGCCATCTTCAATCATTTCAGATAAGACCAGTTGGAAACCTTCCATTAGTTTATCATAAG CTTCTATGAAATCTTTCATAATCCCACCTCTTTTAATGTTTCAGACACATATTTGTTAAT TTTTGATTCAGTAGTTTTAACTGCATGAGGATAATAATGGTATCCCCTGAATGCTGCTAC TTTTTTAGGTTTAGGGACAAAAACATCTTTACCAGATTTATCCACCCAATGCAGGGCTTT TTTATTTTTAGCTGAGAAACTTCCACGACCATCATGAACATATTTTTCATAACCTGAAGG TTTTCCTCTTGCTTTTATAACATACATTTCATCTGTTTCCCTTCTTGCAGTTATTGCAGT TAAAAGATTGTAACGATTGTATTTTATCCTACTTTGAAGGTAAGTTTTAGCATCTTTACT TGCTCCATAACTTACCTTTTTACCTAATCTTGGAGGTACCCGTAATATTTTTTCTTGCAG TCTTTCCCATCCCGCATAATCAAAATCAAAATGTATCATAAAAAATCATCAACTCTTATA AAAAATTAAAAAAAATGTTTAGATTGAGAAAACATGAATCTTAGATTTTTTAATGTAAGG CTTCATTCTTTTTTCAATGTCTTCTGTGAAAATATTGTTTACTGCCTCATCAAAATCAAA ATTTTCATGATCAGTAATTCCCAAGTCCTGTCTTACAGCATGGCTTCTAATAATGTTACT GGTTAATTCAATAATGATTTGTATTACATCATCAGGAATTTTATCTGGTATATCATATTT CTTT TTAACCCAT GATT CCATT GCAGT GTAATAATCATTAATATAAT TATCTAAT TCAGT AGTTTCTAAATTAAATAATTCTTCAGTATTTTTATTAGCTCCACTGTACTGTTTGATTTT TTTTAAGGTGTTTTCATCCAACATAAATTATTCCTATGTTTTAGTCATTGTAATGGTTAA TGTAGTTGAATCATCACCTACAGTATAATTACCTGTGCTTTCAAAGTTTTCATAACCAGT ACATGTTGCACCATATGAATAAACTCCATAAGGAACATTACTTATTGTACAGCCTCCAGC ACTACCAGTACCGTTACAAGTGTAAGTTTTACCATCAGTAATATTTGTTAAAGTTACAAT AGCTCCTTCAACAGGATTTGTTCCATCATCAACACTTACACCAATATTTTTAGTACTAGT TGTTGTGCTGGAGTTTATGCTTCCTTTATGTATGCAAGAGCAGATGCATCAGACCATGCA AACT GAATAT CAGCATACAT T GTAGAAGCAATATAATAC T T GT TAGAT T T TAAAT CAAAT TCAGATTCAACAATAATATTATCAGGATCCGCCAACCATTGAATGTTTTCTTTATGAGTT AAAATTACTGGTTTTTTAGTGAAACCATTACGAAGAGTACTGAAAGCTGGAATTGGTACT AATGGTACTTCCTCAATAATGATGTCCCCATCTTTAGTAATAACTACATCATTAACAGCA TACTTGTCATGATTATCTGCTACATATCTCCATACTGCTCTTTTAAAACTGTATGGTACA AATGCAGCTACCCCACCATCATTTTTATATTTATCAGGGAATAAATCCAACATTCTACGG AATTCTTTTAACGGATTGGAATCTGTTGCAGTTAAATCTATTGTTTCTTGATCTATATCA GAAT CAT C T T C TAAT T T T T TCAAGATACCAT CAT T TAGT T TATAT GAAGT TGCAACATTA GATTCAGTACTTGCAGTATTCCCATAGATTAATGTTCTTTCTAATGCTCTACCATTTGCA CTACCAAATTGACCAGTTAAAGTATTCATGAAATTCTTTTGCTCAATACTGTCATATAAT ACAGTTCTGTGAACACCAGTTAAAGCACGATATTCTTCTGCATCAAAAGCCCTATTAGTG AATGTTGGGTCCTGTTCATTGCTTAAAGTTTGTGGTGTACCACTGATTCTTCCAGCTTCC AAT T CAATAT CAAAAC TCATCATGTC CAAT TCTCTTTTAT GAT T GT GAGT T GGAACAAC T TTAGTCTTGTTTAAAAATGCTGTTTCTTCTTGAACAGCTTGCATGTATTTATCTGCTTTT TCCGCTTGAAGAACTCCTTTACCGAGTTTCCCACTTCCTTCTCCAATATCTACAAATTTA AGGATAAAATCTTCATTATGCATGATTTTATCAGCTAACGCTTGTTCTACTTGTTTAATT GTCATTTTATATCAAACCTTCTCATAAAAAATTTAATTATTAAGTATAATATCTTCTTTT TTTCTACCAGGTCATTCCATTTGAATTCCTACCCATTCTCTCAAGGAATGATTTTTCAGA AGCATTGCCTTTTGCAAGGTCAGGATCAATACTTTTACTAACAGTAGCATCTGGATTAAC AGCACCATCAGCAGTAATAGTAGTATCCACTTTAACTTCTCCTCCATCATCATCTTTTGG AGGTTCTGATTTTTTAACAGCTCCAGGAACAGGATCCTCTTTTGGAGGTTCTGGTGGTTT TTCCCCACCTTCAAGTTTAGTTATCCTTGCATCCATAGTATCTAATCTTTTATCGATTTT ACCTAGTGCTTCTAAAATTTTATTTTCATCTTCCACAGGTTCATTATTTTGTGCTGGAGG TTCAGTTGGTTCTTGAGGTTCAGATTTAGCAACTAAACCATTAATTAATTTTTCAAGAAT ACCTTCTGAAACCTGCACATTATTTTTTCCATTGTCTTCTTTTGTCATAACTTCCACCTC TTCTGGTGTGATATATTTTTTCACAAATTCTTCATCATCTTCATATACTTCAAAAACCGC CATAGGATGTGATGGTTGATCAACAATACTGATTGTTGATGGTTTCCAATCTTTAATGTC TTTAAATTTCAAAGCCATATTTAACCTCCTAATCCTCTACTCATTTGAGCAACACTTTTA TATGGTGCAGCCAGTATGCTGAAACCATTGTATTCCCCATCTCGGATTGCTTGTTGTATT TCCTCATCAGTTACATCAACAGAAATAAACCAGGATCCTTTGGGGTAAGTGTTTCCCCTG AAAGTGGTTGGTGATTCAAGAATATATGATTCTAAAATTCTTCCTACAGGTTGGAGTGTG TGCTGTACATCAACTCCTAATCCCAGGCGATTGTATATTAATGATGCTTGTCTTATTGTT TCTTCATCCAGTATGTCTCCTGTTGCATCAGGGATTCCTGGTATGCAGACTGCACCTTTC ACAATCATAGTTTTTTTTGACTCCCCATTTTTTTATATTGGAAAAAAATTAGTTTTGTTG AC GAAAAGT TAAATAAAT T TAT T CAACAAT T T T GACCATAGGT T TAAAT T GAGGATAT T T ATCAAGAAAATCTAAAGCATATTGTATATGATATTCCCTAGCTTCTTTGTGTTTCCCTTC ATATTTTAATCTATGAGTTACAGCCCGTTCATTCTGATCCAAAGATTCAAACTCCGGATG TTCAATACACTGAATTAATCTTAATCGATTAATATTAGGAATAACTTCACGTACAATACT CATTAATCTATGAGGTAAACCTGAAGGTGTTGTAATGAAATCTCTTAATTGATCCTCAGA CCAATTTTTAACAAATTCATAATTAGGAATCAATTTTTCAACCATGATAATGAACCCCAG TATTTGTTAGTATATTATATATAAAACTTCCTATATAAAAATTACGATATCATTTCCCAA T GAGCAATAAACT CT GAT T T T T CAC GTAT TAAT C T TAAAT CAACAT T T T TAT CAAACAAA ATTTCAAACTCCTGAGGAGTTTCAGTTATTCCTTCAATATACAGAATTTTAATTCCTTTT GGAATGACAATATAATTAATATACTCCCCATATTCTTCAGGTTTAACATTTTCGGAAATA GAAGTTGATAAAAATGAATCTGAATGATAATTATCTCCTTCTACAAATTTAGTCATTGGA CTTTTTTGTCTTCTAACTACAACAAGACTTTCTTCTAATATTTTACCTTTCTTAAATACT GATTTTGAAGATTTAATTGCTTTATTAAAAGAGATATAATATTTTGAATTAGCTAAATCC TGCTCCCATAATTTAGAATATTTTCTTTTAATACGCCACCTCTTAACTGGGTTGAGCTCC CCTTTTATTTCTCTGAAATAATTATTCAAACTATAATATCCTTCATCAGAATATGCTTTT AT GAAT T TATACT CT T CAGAAGT CAAAT CT T CT T T T T TAAT T C CATAT T TATAT T CAAAT GCCAATTTATCTTTAGATGATTCACCAACACCATAAACTGTTTTATTACCAATTTTCACT GCTTTATTTTTAGCTTTACTAAATTTAGTGATAGATTCATTTAATTTAAATTTACTGAAA TCTCTTTTTGAATTTTGTTTTGGTTTTGAAGAAATATTAATCATTACTGTTTTTCTTTTA ACATTTTCAGTGATTTTACTTCCTGTATTTTTAATCTTGTTACCTATATTCGATATGGTT CTAATTATCTTATTCTTAATCTTAGAAGTTATCTTCAAAGAATTTTGATTACTGCTACTT TTATTCTTACCATGTAAGTAAGAATTAGAAGGAATATTAAAAGAACTTTTACTTTTAAGA TTACTTGGAGTACTATTAGTATAGCTTAACCAACATCTGCAATTAGCAACATTCTCAGCA CCTCCAGCTAAATCCCCAGGATACATCATCTCAGTACGATAACTACCAGTAATAATAAAA TAATCATCAATAGGAACACTCTCAATAAAGTTAGCACGATGCCAAATTCTATGTTGTCTA GCACGACCATTCATCCAAACCTTATACTTATACCCCTTATCCAAAGCATGTAAAAAACTC AT CC TAGAC T GAT TAGTAT GCAAAGCAT CAC GAACAATAT T CT TAGCAT T C T TAC GATAC AACTCCCCATACTTCTTTTTAATCTCACTATCAGACAACTTACTTTCAGCTTCAATCTTA ACAGTTTGATCAACACTACCTTGAATAATCTTAGAACGCTTTTTCATTAAAGTATTAGCT TGACCTTGCAAAGCAGTATCAATTATGTTCTCTGCAATCTTTTTACTATTCCCAATTTTA TTTCCATCAATAATATTATTTAATAATTTATCTTTATAAGAATCAATACTTTTATCAGCT TTATTCGTATGTTTAAACAAATGATTAAAACTTATATCTCTTTTAACCACATAAAGCTGA T GCAAT CT T T GAGT TAAAAGCAGATACT GAAGT T T CT T T T TAGAAAT CATAATAAACCAT TCTTATTAAAATCAGAATTCAAAGCATCAATCATACTATCCAATTTACCTTCAGCATCCA TTGGAGCATCACCATACAAAACCTTATCCAAAGACTGATTATTCATAAACCTACAATTAT CCCCTAAAGTCACTGCACCATTTTGCAGTAATTTAATTCCACGATCCAATACTTTATCTT CCTCATCAAAATTAACAGGCAAATACTCAAGTTTATGTGTAAATATTCCAAATTCCTTTT GAATAATAGTCTTATTAATCAAATTAGCCATCCTCTTTTGCAATGTAGCTACTGTAGATT TACTATAATTTTTAAGCAAAGTTTCAGTACGATTACTAGCAATACCTGTAGACTCAGAAT CACCTAAACGTTCACGAGGTACACGATGAATACGACGAATACGATCAGCCACACTACCTG ACAGTTCTAAAAAACTGCCTTCTTTTTTCTCATCAGCAATTTTAGTAACATTAACACTAA CATTATTTTCTTCACTGGGAATAGTGAAAACTAAAGCAGTTCCAGGCTCATTGGACACTT CACGAAACTCATGTTCCAAATCCTCTTCAAAATCATCAAAAGTATAATCTTCTTTTTCCT CAACATTACCTGTAACAGTAATAATATAATTCGGAATACCATGTGCTTTAAAATGCCCTT GCTGATACTCAATAATAGCATTATCAGTTAAAATAGCATCCAACTCGGACAAATATTTCG GTCTACCATAAACAAGACTTTCATTACTTTTAAGATTAAACCAGATTAAATCATTTGCAC GATTTTCATCTGTAATATTATCATCCCACAAACCAGTTTCACGATTCAATTGCTTAATAT TGTCAGGATCATATAATTTGAAATAATTTTCTTTATGCCCTATCTTTTGTACAACACGTT TTTTATCACGACACATTCTCAGGTATAAACTGCTTACATGATTAACACTTTTCAACTCCC CTTTTTCCCTAAGTAGTTCTAATCCTGCAAAACCAAAAGCTTCTAAATCTTCTAGGAATG ATTCTATTTCCTCATCAAAATTAAAATCATTTAAAAAATCATCTAATCCTTCAGGTATTT CTTCTCCTTCTTTAGAGATTATTTTTTTACCTGTGAAAATTGCATCTTCACATTTAACAG TAATACAAATATCATGCAAACCACTAATATCACGCAACTTATCTAATTGGAACGGGTCAT ACGCTGGGTCAATTACTTCTGTACCATATGTTAATTCATCTTTACTCATTTCTTGAGATT TAATCTCATATTCATTTAAAACACTTTTAATCACTGAATCTCTTAAAAAGTTACTTTTAA CTATTTTAACCATTATTAATTTCTCCTTCTACGATTTCTTTTTCTTAAAACTGTAGGTTT TGTTTGAGGATATAAACCTTCATGTAACAATGATACACTATCTACACGGTCATCATGTGT T GT T T CAT CAT CAGCTAT TAT T T T CT CT GAT GGGAAT T T CACAGCT T GT T T CAT GAAAT C TTTCAACCATTTACCACGAACAAATAATATCCGTCCATTATTCATCCCCCGTATAGTTCT ACTTGCTCTTATTAATTTTGATTTAGGAACACGAATAAAATTAGGATGATAGTCTTCGAA TTCGTTTTCCCAGTATCTTTTAACTATTTTACCTGCAGCTGCAGGCTGATACTCAATCCA ATTATCATACTCTGAATGTTCATCCATAATCCTTGTCATGTATTGTTCTAACTTACCTGG CTTTTTTTGTGTGCTTTTCTGATTATGCACTACACCTACTTTTCCTTGTAATACTGTTGA AAAACTACATGCTGTATAATCAGAAGTACTTTTTTCTGTTGCTGCAATATCCCATGTAAT TACTTCTTGAAGAATATCCTTTTCAGTTAATAATTCATTAAACTCTTGTTTGCTAATTGT TGCTGCTTCAATTGTATCATAATCAAATACATCTCCAGCTCTTATTTCATAATCCCAATT ACCAATCTGATACTGATAATCTGCTTTTGATAATTCACGTAAATTAGCTAAGTATTTTTC T T T GT CAATATAT GGAT TAT GC CAGAAAT T CAT T T CAAAAAAAGGGTAT T GT CCT T TAAC AAAT T T T T CAT T TAAGTAT GT T GAT C CAT C T GCAT CAGCAGGAT TAC TAATATAGTAAAT TGCTAATGGGAAAGTCATTAACTTATCAGTTCCTCTGAGACTACGATTCAGGAATTGCAG GTTTACTTTTTCAAATTCTGAAGCTTCATCAACAATGATTTTATGATAAGCACGACTTTT GAATTTCTCTTTGTCTTTTTCCAGAAGCATATATGAATAATAAATCCGTGCATCATTTTC ATGGTTAATGAAACATCTTTTACTTTGATTGTGTTCTATGTAATCGAATGGTTCTGTCCA ATGGTCCAGGTAATCTACTATTCCTCCAGTCGCTATTACATTATCATAAGTAGACCGTAG AATTAAGCAGCGGTAGTATGGTACTTCATAATGTTGTAAGGCTAATACTGCTCCAAGCAT ACTTTTACCAGAATATGCGGAACCTCCAATTAGTTTTCTTGTGTGGCGGTCTGCAATTGC ATATAATTGTCGGTCGTATGGTGTTACTGGAATGTATGGGTTTTCAAGTATTGTTCTTCT AATCAACTTTTTTTGTTGTTGATCTAAGTGTATTTTCTTGTAATCTACTCTCATAATTCA TCAGTGAATTTTTCTAAATCATCGTTAATGGTTAGTAATTCTTCTAATTCTTTGTCGTTC ATATGGATTACATTATCATTTTCTTTGGTGGATGTTTCAATACTTCCTTGTATTTGAGTA TTATTATCTTTAATATCTGTTGGTTGACCATGAGCTAGTCTGAAATTTCTATAGATTATT TCCGCAGATTTATTTAGATTTAGAAAACTATTTGCTCGTGTAGTTGGAGCATTCTCATTA CTATTTTCTTTTAGTTCTTTTTGTATTTCTTTTAGTAATTCAAAATCATCATTGAAGAAT TCTTGAAACTTAGCATTTCCTTGTTTGAATAATTCATAGTTCCACTCTCTTTCTTTTTGA TCCATATGATTATCATATAATCTGCATCTTTCCACCCAATTCCATCTTGAAGAGAGTGTT TTTAGTTGACTTAGTGAAGGTATGTTTTTTTCTTCAGTATGCTTCGATTTCTTCAATTTT ATTATCTGTGGGAATGTTCTTTTGGAACCTAAATCTCTGTATTCTTTGAATAGTGAATAG CTTTTACTTGGTTCTCCTTTTTGTCTTTCCCATGCTTCAGTCATAATCCCCCCATCCTTA TATTTTTTTTGAACATTATTGTAATGTTTATTCTTTTTTGTTGAACACGAAATTTTAAAA TACGGGATTTTTTATTTTCATAGTGAACAATATAATATTGTTTAGTTTTGAATTTTGAAC AAAAAAAAGTTTTATTAGTTTTTTATAATAGTTTTAGGAAATTCACAATAACAAACTGAA ATCCATCAATCAAAAATACAATCAAAGCACCAACAATTGCTATGAATACTCCACTTTTTA TTGTGAATAATCGATTATCATCATTAGCTTGTTCTTCCTGAATAGCCAACTGTTTTGTTT GAATTTCAATACTTTTATCCATTTTCTTTATCAGTTTTTCTAATTGCTTATTTTGAAACT GATCACTTGCTTCCAGTTTACTTATACGAGATTCCTGTTTACAATATTTCTCATGTAAAT CTTGAACTTGATTATGGGTCATTATTGTTTCCTCCATTGTTAGTGGAGGTGTAAGTTCTT GAAATCCATCCAACTATCCCCCCTAATGCTACTGCTGCTAGTTCGTTGTTTCCAATATAG GTGCTTAGAATTCCTATAATTATTATTCCAATTATTGCTAATGTTGTGTTGTTGAAGTTA GTCATTATTATTTTCACTCCTAAAAAAAATTTGTTTTTAAAAAAAACATTGGGGAAGGGA TTTGAACCCCTGCGATACTAGTGTATCATTAGATTAGCAGTCTAACGCCCTACCAGGCTA GGCTACCCCAACATTGTTGGTGGAGGGAATTGCACCCTCAACTTTTGAGTGGTTACTAAG T TACAATAAAAAATAAGCTAT TACCAACAT CAT GAACAT GTAT TAAAGGAGATAAATAT T TATAT TATAT T TAT GGGAAGAATAT T T T T T TT TAAGATAT GT GATAT TAAT TAT T TAAT C T T T GGAGGATACC TATATAT T T TAAT GAAGAAAAAAAT C CAAT CAT T CTAT TAT T CAT TA AAAAT T T GC TACCAT T C CCATAATAAT T T T TAAGAATAATAATAAAT GAAAAGC GAATAA TAAACGGATAAGAATATTATTTTTAAATTGTCAAATAATGATAATGCGAAGCTAATTGTA CAATAACATAT GATAAAATAT T T T T TATAAGT GT T T TAT TACAAGAC CACAT T T T T TACA AACATACTCATCATGCCACTCATCATAGTAAACCTTTTTGCAATCTTTTTTCAGTTTTTC ACAAACAGGACACTCTATTTCTGCATGTTTCATTTTTTAAGGGAAATACACACCCGCAGT T T GT GCAAT TATAT T CT GCAC GAGAT T CAT CCAAAACAGT TAAAGGGGAT T CAGGAAACT TAATATAACAAGATGTCTTATGATTTCTATAATGTTTTTCTTGTTTTTTCCTTTGTTTCC ACTTCCAGTTACAAACAGGACACTCTATTTCTGCATGTTTCATGTTTTTAAAAAATGTAT TAGCATCCAAATAATATTATCCTCCCATATATAATTATAATAATGTCTTTTATTTTTTTT ATGCTCACCACGACTGATATGTCCCTTACTTACAATCCATTTAATCATGGGATCCATCAA ACCTTTTTCATATTCTTTAATAAAATAATTCAATGTCCAAAAAGTAACCTTTTCATTAAA AATTATCCTTTCAAAAAGTTCTTTAGATGTCTTTTTAAATTTTTTTCTATGAAAAATAAT ACTGTCAATTTCATCAATAGTTAAATACAATGCAATATCTTCACCAGAAATATAAATACA TTCCTTATCAACATCATACCAATAATACTTCTCATTAGGATTTCTTAATAATTTAAGATA CTTGATAAAATTCATATTTTTACTCCTATTCTTTTTAATTCTCTTTTCACAGTTCTTTCC TCCAAACCAAAATCACTCAAAGCATGCTGTGAAAGAAATGTTGTACCAGGCTCCCTTAAC TCATTACTAATTAACTCCCCATCATTAATTAATTTCCTACGTTTTTGTTGATACTTTGCT TTCTGCTCACGTACCGCCCAGGTCCTGCAAGCTTCCCTGCAATAACCTGTTTTATTCTCA AACTTAATAAATACTCTGCCACAGTATTTGCATTTGCTGATGTAGAATCTTGTTTGTGGA TCATTTAATGTTTTCTTCAATAACATCCTATCATCTTTCTAAATTTTTAGATAGTAAGTT TTTCTTCACTTCAAAAACAAACATGTGAAAAGGTAAAAGTTTACCCTGATATTTCACATA TTCATTAATTACTTGTGATTTTTTTAATGCTTCAGTTATAGTTTCTTGTTTTAATTCTTC ATTTATGCATTCAAAATTGGAGACTGTTCTACTTAAACTAATGTATACTCTTTCATATAG ATTAAGGTTATTGTTTTTCACATTCTCCAC CACAACAAGAAAC T GAAT T T T CAGAAGT GT T GAAT T TAC CAT C T T CAAT CAT T T CAAT CAACT CAT TAAGAATAC GAGTAACAT GCAT CA AAGTATGAAGATTAATACTATGAATTATAACATCATCATACTCCATGTCTCTCAAACTAC CTGTGCATTCTTTATGAATAGTAAAAGATTGTTCTTCAAATTCCCTGCTTCTTGTTTTAA TAAAATATAGTAATAATTTCTCATCAATCATACATATTTATCCTCCATGTATTTTTTAAC TTCTTTCATAAAAACTCCTGATTACAATATAACCTATCTTAATCATCAAAAAAATCAGTA AGACATAACACTAAACAACAACTAATAATTACACTTACACTAAAAACTACCCAACCATCC ATCATACTATATTCTCCCCCCATTATCTCCAACTTGTTATTAACTCATACTCCTCATGAG TTAACTTCTGTTTTAACCTTTCATCAAAACTTCTTACATCTCCAGGATTATTCTCATCCC AACAAGACTCAATCTTGGCAGTTAATTCATTAATTTCTTCCTTATTCATTTTCAATATCC TCCTATTTAATTTTGAAAGGTTGTAATGGTAGTGTTGGTCTTTCAAATATAATCTGAAAC AAAACAGTATCCCCACATATATCTGGATAAATACTTTTTAACTCATGTTTCAACAAATCA ACATGCCTATAACCTTCAAACCAAGCATGATTATGTTTCAAATCTTTAAATTTAACCTGT TCAACTCTCCGTACTACCCGAAGCAGACAAAAACCCGTCCCCTCAAACCAACATTCTACA AGGTCACCTTTTTTCAATCCTTTATCAGATTTTCTTATTGTAGACATTTTTTTCCTACTT CTTAAAGGTTCAAAGAAATACGGTTTAAACTTCAATGTTTTCATTTTTATCAACTTCCTT TTTTACATATCTTTGCTTCTTTTTTATCATCATCCAACACTATATTATGTTCTTTTAGGT AT GAT T T T C CAAATAAT T CT T CAGCAT GT T TAGATAACAGATAAGAAT CAAT TAG T CCT T CAGCAGATATTATTCCTTCTTTTTCTAATTTTTCAAGTATATCATTACAACTCATTTTTG GATCTCCTTTTTATTCCGGACTGGTTGTCTTTGACTTGGTTCAGGAACACCACACCTCAT ACGTACCTTTTCAGCAAACTTAACAAACTCATCTGCAAATAAACTTATTCTAAACCACAT CAACTGCCACCTTAATATAATATGTTCCTCATCTTCTTTCTTCATGATTCCACCTTTTTT AACCTAGTTTGGAAGTTATTTCCCCCATAACGCCTAACATGATCTTCACAAATGATTCTT TTCACAAAGGAATCTTTTTGATGTCGAGTTAATCCATACCTTTTCTGCAACTCATCAACA GAGATATTTAATTCATGTTTATAATCTCTCCTGAATTTCAAATATGTTTCTTCACCTTTA GAAACATCATAATCCGTTTCAACAATATTAAAAACTGGTTTATTCATTTTTTATCTCTCC GTATACGTACGTACGTATGTGCACGTACGTGGTTTCCTACAGGTTCTTCGGAAAAATGTA AACATAAAT GT T TAGAAAT CAT T T TAT CAC CAAACCATAAT T C C GAACAT CATAACCCAA ATCATACACATGATCCAATAATGACTTATACGGAACTTCTTGCTGCTTACTAATATTCTT CAGCTGATCTTTACCAATAAAACCAGCATTATCAACAATCCTATTAACTGTACCCATCAC CCCATCAAAGACATTTACACTTCTTTCATGTTCTAAACGCTCAGCACGAATCTTACATAA TCTTGATTCACGAGCATTAATCTCATTTTGCAACTCAGCTATCTCTTTTCTCAAACTATT TTCCTCATCTTCAGATAAATCAATAGCTAATCTTAACTGCTCTTCTAAAAACTCACTTCT GGTTGTCCCCAGTTTGTTTTTAGCTTCCCTCCATACTTCAGAATCAACCATGAATGAAAC CTGTATTTTTTCACTCATACATCATCACCTAACTCTTTCATGACAGTTTCTAATTGCATT TCCTTTGCAATTAAATCTAATTTTAAAGACCTGATTTCCTCTTTTAACTGGTCCTTTTCA AT TAACCT T T GAT TTTGTTTACT GAGATACATAT CAAT GCAAT GT T C CAC GCAGAAAC GT ACAGTTAAACCATACTTTTCCATTAACTTTTTTGCCCTTGTAGTAATCCTACCAGATACC ACTTCAGGGAAATTATCCTGAGTATTCATACTCTTACACCTAACATTTTTTCTGCTTTTT TAATATGTTTGCATTTATAATGTTCTACTTTTTGATGTCGGTAGAAATAATCTTCACAAC TACACCACCATCCATCTATACTGTCCCAGTTCACAGTATTGGATCCAGTATTTCCTGATG CCTTGAATTGTATGAATATTATTTCTACCTTAGGTTCCATAATTAAACAGCAACCTCTTT TTCTTGATTTTTAAACCAGTTATATGCTTCTTTGTTTTCAGCTTTGGTCAGTTCACCATC T T T GAATAACT T CAT T C TAT GAGTAT TAAT CATAGAT GGAGT TAT T T CCAGT GAACT GT C CTTTTTATGAATATACTCGCGGATTTTCTGCACAGCACCAGTAGCCTCAACTTTCTCAGT TCTTGCAGAACTACCCTTAGCAGTTTTAACATTAATTTTATCAGAATCCACAACATCTTT TTCAACAATTAGAAACATGTTTGCTAATAAATATCTTTTTAAGTAAGTAATGTAACTGCC TTCACTTTGCATTACATTCATACCTTTATTTAAAGCAACTATTTCAGGCATAGGAACACT GGT GAT GAGAGAT TCCCCAGGTTCATTC GAAT T T C T GAT T T T CAAT T GAGC GAAT T CAT T T GTAAAT GAAAAC T GAAT GAATAACT GGT GT T CATAACAT T CACAAAAGAT T GCAGGCAA AATATCTTCTAATTCATAGTACTTAAATTTCCCAAATTTATTGTACCCACTTTTAGGTAA T T T T T TAT GCAGGAGAT T CT T T T GAAT T CC T GCAAT T T T CT GATATATAGT CATAAAAAA ATAATCCCCCTTTTTACATATTCATCGACTTTTTCATCAAATCCCTAATTTCTTTTAACT GT T CAT T T T CACT TAT T T T T CTAAACAT GGT GT T CAGAATATAT T CAT C GTAAT C TATAT TTTTTTCAGCACATAACTCTTCCATCAGTGCTTTAACTATTCTAACTTGATTTTTCTGTA CAATAT GT T TAAAGAT CATAT CAAAAAAT GAAT T CAAT T CT GCAGGAT T T T TAGCAT CTA CATTATGGTCTAAAAAGTGGATTGCATTAGTTAATTTCTCCTTTAACTCTTTTTTGTTTA TGATTTCTTCAGTAAATAGTTCTTTCTCCATTAAAATTCCTCCTCAATAATCTCCAATAC TTTGTTTTCATCAATATTTTCCAAAGATGCTTGAGAGTGTGGAATGAAACTTTTTGACAC CCAGTAGTCATGATACTGGATTTCACCACCACACAGTTCCTGTAAAGTATTCATAATATC ACGTGTGTTCTCATAAGTACTGTCATGAAAAACAATTACAGATAAGAAAATACCATGTAA GTTTCCATGAGCAGAAATACGTCCGCCCATTTTTTCAACAATTCCTAATAATTGATTGTA AAACCTGTTTTGCTGATCATAAGTAATCATACTAAACACCCATTATTATAAGGATCCATA GGCCCTACTACAAGGAATGCAAAAATGAATAATAAAATTATTAAAATTATTCCTTTTGCA AAGATTATTTCAACTTCATACTTTTCTCTCCAGGACACTTTTTTATGAAGTCTAACTGGA GTAGGTTTATTGTTGAAGAGACTCATAATTGAGCCTCCAACACTTTATACTTAACTTCTT TTTTCATACCAGGAGTATTAAGGAAATCTTTCAATTCCCTTAATCTGGTTTGTTCTTCAA CATACTCTGCATACTCCCCGTATAATGTTTCGAACAATTCTCTTTGTTCAGGATATTCCT GTGCTAGAAATACGAACAGTTCATCTATTTCACAGTAATCTTTGTACTGTGACTGGTTTA TACGATATAACGCATTACCAATCTTGTTTTCATTTTTCCAAAATTCAGGAGTGAACATTC ATTTACCCCCGTAAGCTAGTTCACCTGCACGAGCAAACTCCAACATTTGATCATCAGACA ATTCATAGATTTGAAATTGCTTATATTCATCAGCCAACCTATGATCTATTTCTTCCTGTG TTTCATAATCCTCAGACAATAATATCTGTTCAAGATAATCAAACTCGACCTCATCTTCAG GTGGAGTAATCGTATACATTGAGTTGTTGTATCTGCAACTCATACGCCCACACTCCTGAA TTTTTGGAGTTCTTCTTCATAGACTCTGTTTTGAGCCTGAAGCCTTTTTGCTTTTAAAAA TACATGTTCAATTTCTTCTTTGGAAGTTAACCTTCCAAAAACTTCAATCTTATTATTATC CATATTACCAACTCGTGGATTTTTTAGAAGATCTTCTTCAGAGTTGCCGCTCTGATTTTT TCTTCTTCAAATAACTATTATACTTAATACTATATAAAGGTTATTATATTTACCTTTATT AAAGGTAAATATATATACTGCAAAACAGAATATATTATATAAGAAATATAAAAATGGAGG TATGCCTATTTTAGAATATACAACAAAATTAAGTAAAGGCGGACCTAATTCTATTAGGTC AATAGTCCCCCAAGATGTGATAAAATTATTAGAATTAGAACTGGGGGATTCATTACATTG GATTGTAAATATTGATGAAGGAATAACTGTATCTATTGAAAAAGCTGAAAAATAATCAGT TAATCCTTCACAAATATTTTTAGTAAATATTAAATATCTTTTTTTATAATAAATAGTATT GGTTACTAAAATTTTTATCAACTCGTGGTATCTATTTTTTGTAGCCTCTAGTTTTTGAGA GGCGAGATGTTGCCGCATCACAGACCCCCTCATCAACTAGGAATTACATTTACTTATTTT GCATTTAATTGTTCTTTTTCAACCTTTTTTTGTTCTGATAACATCATAAAATATGTAAAG TATAATCTATTTACAAAACCATATTCCCCACTATTTTCTCTCCCAATAGACTCTATAATC CCAAGGTCTTTAGCTCTCTTTAAAAAATCATTAAAAGCTCTCTTCTCCCCATTTGTCAAA ATATTTTTCACATCTGATTTTTTAAAATCCATTAATCTATTTTCCCCTAATTTAAGAAAA ATATCAATATATGTATCGCTTCTAATTTTATTTAATTTGGATTTTAATTGTTTTTTAGCT AAT T CAT CT GT T GCAT CAGTAATACCAGAAAATACTATAGAT T CAT T TAT T T T TAAAT TA TCTTGAGCATTCCAAAAAATTGAATCACCAATTTGTTGCATTATTAAAGGCATACCCCAT GAAAAATAAACCATAGGTTCTATAGAATTATATCCATCTTCAAACTCAATGCCTACATTA TTAAATGAAGTTGTGAAGAAATCTTCAATATCATTATCCTCTAAATTATCAATTTCAATT AAAT TAAACAT T C TAGAAAAT GAT T CAT TAAT T GAACATAAT T T T T CAAAT T CAT GAGGG TAAC T TAT TAAT GT GAAAACAACAGGCATAT GATAT T CAT TAACCAATAAT GT T T CAGAT AATCCTTTATACCAATCTGTAAACTCTTCATTATCAGATAAACCATTAAGATCATCAACA ACAATAAATATTCCATAATCTTCAGGTAATTCTTTACAAGTAGTAATCAAAAAATCTGCA AAAT GT T T T T TAATAT TAT GAAT TAAAT TAGTAT CAT TAT CT T T TAAAGATACT C CAGT C CCTGCAACTTTAAATTCATTAATATTATTCAAAATTTTATCAATTACACTTTTACCTAAA TAATCCTTTTTAAATTCTTTTAATAATCCATCAAGTAACTTTTGTATTAATTCATCAATA GTTTTTCCACCACCATTGTTAATATGGATTGGAATCATTTGAAAATCATCTTCTGCTTTT CTTGAAACATAATTTATAAATGATGTTTTACCCATTCCTCTCTTTCCAGTTATGAAAAAA TGTTCGGGAGCTCCTTGATTTTTAACTTTAGGTAAATATTTTATAATTTTGTTGATATCT TCTTTTCTTCCTTTAAAATTATCTGGAGATACTGGTCTCCCTGGTTCAAAAGGACTTTCT GGGAAATCTTGTGACATGATATTTTTACCCCTCAATACTCATTTATTACAATTTACATTT TGTATTTAACTGTCTTATCAAATTTTTATTACTGTATCAGCTAGAAAATCTGGTGTAACA TTCCGTTTCTTTTTTTGATTTAAAATAGTATTGGACCATTTACTGAACTGTGTAGCTTCT TTACTATTGACGCGATAGCCTACGGAAATCATAGCATCTAAATTATAGAGTATGGGTTGA GTATTTGCTTCAGGATTAATTTTAATAACGATTCCACTAATAGTGGAATCGTTTGGATTA ACAGTTACTTCATCTTTAACAAGTTCTCCACTATCAAAGATATTATTTAAATGTTTACTA ATGTTTTTTGGTGTTTTATTAAATAAATTAGCCATTGTTTTTTGTGTTGCCCATAATGTT TCGTTTTCTTGATCAATGATAACTTTAATTGATACTGGCCCATCTTCACTTTTATATAAA AATGTTTCAATAAGATTACTTTCCACCATGATTTATATAACCTCTACAATTTTACTCTTC AAAAAAGTTTTTTTATTCTTGTTTTTATATTTATGTTATAAGTTAATATAAATGTTTCTA TTCAAAAAATAAACCTTAAAAATACAGTATATTCAATGAAAATAATGAAACACTAAACAT TATT CAGTAT GAAAAAAT GAAACGCATT GT GTTCTAAAT TTT GGT GT TTAATTAGTTTT G TGAACTGTTAGGTTATTGTTCATTTTTATAATGAATATTTTTTATCTTTTTTTGTTATTA AAATGTATTGATATTTTTAATTAAAAAAATAGAAACCTTTATATACTATGTAGTACAATA TAATAATAGAAATACAT GGAGGT GAAAAGT T GT CAGAAT CAGAGGCAATAAAAAT CATAA TATTGTCTTTGAGTATAATCCTAGAAATACTCAAAAGACAAAAACACAAGTAGGAGGTTA ACCCCCTCTTACAATTATTATATTTTTTATTGCTTCTTATATAAATTTTTCTTAAAAAGG AGGT GAAAAACAAAAT GACAATAACAAGCAT CATAATAC TAATAT TAT TAAT CATAT TAG CAATATTAATCTACATTAATAGAAACCAAAAATATACTTGGATAAGTTTAATAATATGGT TGGTTATTTTAATAAGTTTCATCTACGAAACATTAATCTAACCCCCCCATATTTTTTTTA TATTATAAGCCAAAAAAAAGGAAGATGATAAAAAATGACTGACTACACCAGCATAAGAAT AAAAAAAGAAATAGCTGAAAAAATACAATTAATAAAAATACAAAACAACTGCAAATCACT AAACGAAACACTAGAACAACTAATACCCCGAACAGTAAACGAAAACTACGAGTTCATAAA AGAACAACCAATATTCACAATAAACAACAAACCCATAACATTCACAGACCTGAAAAACAA CAATACAGGCAAAACATGGGGAAATGAAAAACAAAACGCAACAATAGTATTTAAAGATAA ACAAGGAGCAT T TATAAGAT T CAAT GAT GAAGAT GAAGTAT T C T TAGAATACTAC CACT T CATCTAAAACCATTCTTTTTTTAATATTAAAAATAAATCCATAAAACCTCAAATTTTTAA AGT T T TAAAAAT T T GT T CCATAAGGTACATAGCAT CAT C CAAT T CAC CT T CAGAGATAT T ATAAAAAGGATCATAATCTGCTTTTTTTCTTAAATTAAATAAATCATATAGTTTATTCCT AACAGAATACT GAT T GACCT CAAGAAGT T CATAT T GAAC T T GC CCAT GT T C T GTAATAAA CTCATTTTCACCAAAGTCTTCTTTAGACAATGGTTTAAATTTATAAACTTCCTGAAGCCA CAAACTAACATATAAATAAGCACTGTAATAGCACCTATTGATAATAGTACTAAACACACA AC GAT TAT C GCAAT T T T CAGGGAT TAAT TCTTCTTTATTTT CATATAACT GCT TAGT GAA TTTATATAATTCATATTGAGGGTATTTTTCAATATTAATGTATAAAACCCCCAATAAATT ATTTAATTAAAATATAGGTATCTTTATAGAAATCAAACATATTATTTTCCTTTGAAAAGA TAACCATATCATTAATAATTTGGTCTAACAGAGAATATTTTTCTTTCCTATCAATATGAA AT GGAACAT TAAT T GTAAATAC T T T T TCAGGATAT GAT C CAT CATACACT GTAT CAATAG ATATATTTTTTCCTAATCCTAAATTGTCAGAAATTTTTATAAGTTCATCATAAAATTCAG TGATTTTACTTTCAAAAGACTCTGTGGATGATTTTTTAAAAAACTTATTTTTAAAAAAAT CCCCTACAATATTAGAAGGTTTATTATATCCATAATTTTTATCAACTGAATACACCATAG ACACCACCTATAAATGTTTATTCTAAAGTTTTTCTAATAATATCCAATGTTTCAGGATTA TTTTGAACATCAATAAGAACTGTATTACTTTTTATTTCTTCATCATTCCTATAAGATAAA GTAAGAATATCCTTATTTATTTCCCCATCTTTTAAAACAAAAGCTGCATTTATAGGTATA ACTTCAAGATTTTCAAAGTTTTCTTCAAGTTTTTTTAAAAAATCAACATTAAAAACTTCT TTAAGGGAAATCCCCTCTTGAAGCACTCTTAAGCTTCTTGCATCCTTTTTCATTTAACTT CCTCCAAAATAGTTATTTAATAAATATCTTTTATTAAACATATAAACCTTGTCAAAAAAT TTTTAAATTAATAAATCTTCAAAGTCATTTTCTTTGAAATTTTCTTCTTTTTTCTCAATA TTTCGTAATCTTTCATCAATATCATAGATTAATTTTTCATAATCTTTGATTTTTTCATCT TTTTCAACAATTGTATTTTCTAATTTTAAAAATTCTGGAGATTTAACAGTGATCTTTTCA ACTTCTTTACTAATTGATAATGCTGGTAAATGTTGAATATATTCCTGTTTTAAATCAGCA GGAT T GGT CAT GAAATATACT T CAT CAGTACT GT T T T T TGAT T T GCC T T GCAGGT CAT T T ACTTTGTCCAGACTCATACCATCATTATATAGTGTTGAGGCGTGGAATTTTCTGAGCATG TGGCTGCGGAATCTGTTGTAGTTTCCTGCTTTTCCTAATCCTAATTCATTGTTTATTTTA ATGAATTGTTGGTTTAGGTAGTCTTCATGTATTTTGAATAGTTGGGATTCTGGTGTTAAA TTTTGTCTTGATAGTAAGTGATGATTTATAGCTGTGACTGCTTCTGGACTGCAATAGGTA ATATAATATTTCTGTGTTTTTTGCCTTAAAATATTAAAAGTAGGGACAACATTATCAATA TTATTTAACACATCTATCATTTCCATAATATTATCTGTATTATGGTATTCTTTAGTTGCG TTCATATAGTCCATTACAGTTAAATTTAATGTTTCTCTTCTGGCACAACCTGAACTACTC ATGAATAATATAATAGCTTTCATGGTAGAAGTACATATATTAACTGCTTCACGAATAATT TCTTTATCAGGTAAATCTTTAAAACTGATCGGTTTGGGATTATTATAACTTTTTTTATCA AT T C GT GGCAGAT CAT GTAT T T CAAT T T CAAAATAT T TATATACAACAAGAACT GGT GT G AAAGTAT T T GATACAGT GT TATAATAATAAT TAT CCAT CAAATACT T GC GAAAAT T TAAT AATCTTCTTTTTAATGTACGATGTTTCCATCGTATACCCTGTTCTTCTTCTTTTTCTGCT TCTTCGATTAATTCGGCTAATGATAACTTATTCAATTCACAATATTTATTTATTGAATGT TTGTAAATATGCTGTGTTGTTTTTTTATGATTTTTAACAGAATGGATCTCATTTAGGATT TCTTCATTGGTTCTCATATTTATCAAATCTATTTTTCTCTTTTTATATTGTTTGATGTAG AGT GCAT T T GATAAGTAT GT GATAATAT GT CTAC T GT C GT GT C TAGAAC GAGT TAAT TAT AACATACT TAAAACAT T CTAAT CTAT TAAAATAT TATAT CAAAAATAGGT T T TAAAT T T T ATAAATTTCTCCGTATTCATCTTCAAATCTGATTAATGCTCCAAGGTTATCTTTATAGAT TAATGTTGCTTTTTCCCCATTACTCCATTGTGTGCCTACTTCCGATTGTTTTAATTCATT CCATGATACATTTAAAACTGTTTTTTTGTTTATTAGTGTGAATGCTGGTTGTTCTTGTAT GTATTCTTCAGGTGTTGATGTTCCATCAGGTAATAAATGTTTTACTGTTTCATTAACTGA TTTGTATCCGTTGATTTCCTGTATTTCTTTTATCTTGTTAATTAAATTTACTTCAAGTTT TATAGTACTTCTTTCCATTATTTAATTCCTCCTTTAAAAAAATAATAAAAAAATTATAGT CTTTATATTAAATGGATTATAATGATGACTATAATATTTATTATAAGCATTATTGCGTTT CGTGTCCTGTTTTCTTCATTTTTCATTGAATATAATAATACTACTGCAAGTATTATTAAA ATTATTTGAATTAATGTTAATACTGTGGTTATCATAATTCCCCATCCCTTTTATTTAAAT ATTAGTAATGACATATAATTTATTATAAATTATTTTAAAGAGGGATTAATTTTAATCCCC CATTAGGGATAATATTATTGATATTATCCCCATAACCATATTTATTAGAAAATATATGTC ATTTTTATCAATGTTTTTCACCTCCTTGTAGTTCTATTATTATATTGGTTACTATACTAT ATAAAGGTTTCTATTTTTTACTACTTATTTTTATAAAAAAATAAAAGAATTGTTGATAAA ACAACAAT C T TAT T GAT ACAAAT C T GAGAAAAT CCAAGCTGGATCATAC GC TAAAAT C GT ACCATTCATACACCAATTACTTGAAACACTGTTTCCATCTAAAACTGCTGCAGGGTCACG ATAAATCCAAGAACCCCCAGTATACTTAGAATGTTTCAATCTGAGCCTTACATGCCCAGT CCCACTTCTACATCGTACATGAATGAATTGTACATTATAACCTAATGCAAGTCCTAAACG GTAAAATAATTGACTTGAATCAGTACAATTAACTCCTTGCTTATTATATATCTTATTAAT AGTTTCCTGAGTATTATATTTGGAGTTATAATAATATCCATATCCTCTTCCTCGGATTTT GTTCAAGCAAGAGTCTATATCTGTTACACCACCAAATTTGTCGGTGAACCTTTTTAATGT GATGTCTGTGGTGTCGCTGGTTGTTCCGTTGCCATGTGGGTCTTCAAGATAAACAATAGC TGGACTAACACCATTTAATACTTCATAAGCTGATACACGATTAGCCATACTAACATAACA ATTCTTATAATACTTTGTTCCATCAGTATCAGACACATAATTTGGGAGGAAACTTAAATC TTTATTATCAAATATTGCACATTCAACAAACTCTGCAATAAGACTGTCTTGTTGATAATT CGTACCTCTCTCTTTAATTGCTTTTATAATTGTGCCATAATCAGCTACACGATTCATGTA ACTATACACTTGTCTTGTATTAAACTTTTTATTATTATTCACTAACCAATAAGCAATTCT ATTCATCAAATAAGTGTATTTTGTAAAACTAATATGTTCATTAACCATTTATTTTCATCT CCTTTTTAAATTTTAAATCATCTAAATATTCCTTTAAAATACTGCATTTTATTATTGCAT CT T CAAAACAACAAGGAACCT C T T TAT CACAAGGAT CATAAAAT GCACAT T T T T CACAT T CTTCACTAATCATTCCAAAATAATCCTCCTATCAATTTTTAATGTACAATCAGTAATCTT GTTTGTTCTAAACGAGGATTCTCTCCAGCAGCTCCTCTTTTTACAATACCTTCCAACATA TAACTTCCAGGGTCTAATCTAATCGGCAGTATTGCTCTACCATTAGCATCAGTTGTTCTT TCATAAGAAACACCATTTACAATAAAATTAATTACCACATTTTCCCCTGTGTTAATTTCA GGATTGGAAGAAATAATTTTACCGTAAACAGAATTTCCATAATTTAATTCTAGTTTAACT CCATCTTCTCCAGCAAGGTCTGATAAGCGACCCATTACTAATCTAGTGTTTTTTAAATCA TCCATTGTGGTTTCTAATATTTCTTGTCTTGCAAATGTTTCAGAATGTTCATCATCCACC AAATCTGCATTTAAACCTGAACCTGCTCCATCCACTTCTTTTAATTTATTTAAAATAGTG GTGGGTGTTTCAATGTTTCCATCTTTACCATCTTTTCCTGCAGGTCCAGTATCACCTTTA CTTCCTTTATCACCTTTAGGACCTGTTGGTCCTGTTGGTCCAGTATTGCCTTTAGGGCCT TTGAAATTCCCCAGTAATATTTTTTTAACCATTAAAAAAAACCTCTTCATTTATTTAATT ATACTCCTATTTTCATTTTCACACCAGACACATTATAACTCATACTTGTACCGCTACTCC ATGCACCTGCTTTTGTAATTAATCTCCACCTATTAGGATTAATTTCTGCTCCTCGACTCT TATTGGCTGTGTTAATTGTTTGAGAATCATCACATAATACATAACTTAACTTATCATGTC TTACTTTGAAAATTAAACCAAAATATTTTCCTGCAACATTCCCATATGTGCCCTTTTGGT CGTAAGTTCTATTTGTTCCACCATCACAAACTATATCAACCCATGTACGGCCTTGCTGAG GGGTGCATACTACACTTATTTTTTCGTTTGTTTCTGGGTTCAATAAGATAAATTGTATAT TAGAGTTAGTTCCTAAGCTGTTAGGACTCCATGATAAAAATAAGTCAAAGTTTTCAAGAT TAAAAGTATCTGTACGATACCCTTCTTGAGTGCTCTGCTTGTAGGGTATTTGTATGGTAT CGTGAACATGTGAGTGAGTAATACTTTTATCTGCAATACTGCTTCCTTCAGGCAATATAA CATCAGATAAAAAGAAACTAAAATCTCTTGTATTAATATTGGTTTTACCATCCAAGCTTG ATTGAAGATCAGTAATATTGCTGATACTGTGACTGTGACTATTGTTAGCTTTACCGTTCA ACGCATTAGTCACGATTTTATTCTGTACAGGATTAATAGAAGAACTACTTAATGATGAAT CAACAACT GT T T TAT TAGCACCAT CAT CAATAT T T T CCAAT T T T T TGT CAT GAT CATAAA CAAAACCATTTACACTTGACTGTCTATTAATTCCATATTCATACACCCACATGCCATCAT CACTATCCTGATCAAGGTCTATACTATCACTTGTATGGCTGTGGTTAACATTTGCTTTAT TTGCTAATTGAGTATTCATTTCTGTTTGTGTAACATACCCTGATAAGTCAACTGTTGTTT CAGT T GAAC CAAT T T T T TCAAAT T TAT TAT TAAC CCAAATATACT CAT CATAAATAT TAC CCTCAACAGAAGCTGAAGTATTTAATTTTAAATACATTACTCCAACTTCCCCTGTAGATG GTAAT GAAT T TAC TAT T GT T GC T GTAAAAC CAAT TAAT GAAT T TAT C T GAGAAT TAATAT TATTTACTTTCGCATCTATTTCAGTTTCAGTATAATACCTTTCATCATGATTATGTCCAA CATTTGATTTTCCACCTAATTTTGAATCAATTTCTGTTTTCTTATAATAATCATTTAAAT GTTTAACAGCAATATAATTGCCAACATGTACCTGATAACTATTTGCTCCATCTTCACTAG CTATATTTAAATATAAATCACCAGTAGTTTCATCATGTTCAAATATTGGAGGGTTGGTTT CATCATTACAATAACACCATAGATTTCCTTCAGCATCTCCTGCTAAAGTGAAAAAACCTG GTGGAGGTACTGTAATATTTAATAATGGGTTTGCCCATTTGTCGAACAATTCATCAATGG CTTTACTTACTGTATTGGCATCTGTCTTTAATATGTCGATGTCTAGGAAATCTTCAATGT TTCCTATTTTTGTGCCTAGGTTTGTTTCTCTTAATCTTGCACATGCATTATTTAATGCTT TTCTTTCATTTTCAGTTAGTTTAGTCATATTACACTCTCTCGTTTAACATTACCTATTTT AATCTCTTTGTCACCATTTAGATAAGGATTATAACTTATTTCTGTTATTTGTGCTTTGAA CACCTCTGAATCTGGGAATCTTACATATAC In preferred embodiments, the pharmaceutical compositions of the invention further comprise at least one additional virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract of a human. Similarly, in preferred embodiments, the methods in which the viruses and pharmaceutical compositions are used comprise the administration of at least one additional virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract of a human. In preferred embodiments, the at least one additional virus is a virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract of a human selected from those disclosed herein. The viruses may be stabilised as discussed above. Archaea and bacteria are known to develop resistance against particular active substances over time. It is therefore advantageous for pharmaceutical compositions and methods to involve a cocktail of two or more viruses to minimise the impact of such resistance. The use of two or more viruses in combination is additionally advantageous because, as discussed above, viruses are specific to their target bacteria and / or archaea. Thus, unlike other methane-inhibiting agents, which provide a less targeted approach and can cause toxicity to the human, viruses will not cause problematic off-target side effects for the human. Further, 18 the use of more than one virus reduces the risk that archaea and bacteria have developed or will develop resistance to the active substance. In preferred embodiments, the pharmaceutical compositions of the invention further comprise at least one additional active substance which alleviates the symptoms of irritable bowel syndrome. Similarly, in preferred embodiments, the methods in which the viruses and pharmaceutical compositions are used comprise the administration of at least one additional active substance which alleviates the symptoms of irritable bowel syndrome. In particularly preferred embodiments, the additional active substance is an antispasmodic. Preferably, the antispasmodic comprises hyoscine or a pharmaceutically acceptable salt thereof. The co-administration of additional active substances which alleviate the symptoms of irritable bowel syndrome is advantageous because this allows for a more complete reduction in a patient’s discomfort and symptoms. For example, a patient’s constipation may be reduced by virtue of the administration of the virus of the invention, while their abdominal pain may also be reduced due to co-administration of an antispasmodic. This provides a more complete treatment. In some embodiments, the compositions of the invention further comprise a clay, preferably Fuller’s Earth. In some embodiments, the compositions of the invention further comprise silica gel. In some embodiments, the compositions of the invention further comprise fibre. In some embodiments, the compositions of the invention further comprise probiotics. In some embodiments, the compositions of the invention further comprise one or more food additives. In some embodiments, the compositions of the invention further comprise one or more dietary supplements. In some embodiments, the compositions of the invention comprise one or more of a clay, silica gel, fibre, probiotics, food additives and dietary supplements. In some embodiments, the pharmaceutical compositions of the invention are configured to provide location-specific release of the virus to the human. This is advantageous because it allows for the targeting of particular parts of the body for treatment. For example, the pharmaceutical composition may be configured to provide location-specific release of the virus when the pharmaceutical composition enters the target release area (such as the small intestine) in a patient’s gastrointestinal tract, thus allowing for targeted reduction in methane in the parts of the body where its production is most problematic. In some embodiments, this is achieved when the pharmaceutical composition is in the form of a tablet which is coated with an enteric coating or, more preferably, encapsulated in an enteric coating. The enteric coating protects the active ingredient (i.e., the virus) from the acidic pH environment in a patient’s stomach, preventing it from being released. Once the tablet passes into a patient’s intestines, the coating breaks down to release the virus in a targeted way. EXAMPLES Example 1 A virus with activity against Methanobrevibacter smithii was isolated from abattoir specimens of fresh bovine rumen fluid that had been concentrated by filtration and addition of polyethylene glycol (PEG) and sodium chloride to a final concentration of 10% (w / v) and 0.5M, respectively as described below. First, virus particles were separated from the rumen fluid, concentrated and purified using PEG precipitation and centrifugation. Archaea cultures in 119 Broth were inoculated with the purified virus suspension and the cultures were allowed to grow for 48 hours to allow any Archaea specific viruses to initiate a cycle of infection and amplification. Following incubation, methane production was measured using gas chromatography-mass spectrometry (GC-MS). Cultures inoculated with the virus preparation were compared to those that were not treated with virus, but were otherwise identical. The presence of active virus was confirmed by a measurable reduction in methane production in cultures exposed to the virus preparation. The viruses released during the infection cycle were recovered from the cultures by filtration with a 0.22pm filter that allowed the separation of virus particles from the Archaea in the culture medium. The recovered virus suspension was then used to inoculate a fresh culture of host Archaea cells as before. This process of infection, replication, extraction and re-infection, referred to as passaging, was repeated four and six times to obtain a virus with activity against Methanobrevibacter smithii. The virus with activity against Methanobrevibacter smithii was a novel virus which had the sequence set forth in SEQ ID NO:1. Fresh human faeces obtained from three healthy donors were used in an established in vitro colon model to investigate the methane mitigation effect of the virus which had been demonstrated to be active against Methanobrevibacter smithii (ATCC 35061). Because the nature of the intrinsic archaea population within each faecal donor sample was not known, a spike of Methanibrevibacter smithii (ATCC 35061) was introduced to the in vitro colon model to provide a sensitive target for the virus. The in vitro colon model comprised 100ml volume, acid-washed, sterilised, air-tight, glass vessels with sealed rubber lids which could be manipulated in an anaerobic chamber containing a standard anaerobic gas mixture of 80% nitrogen, 10% carbon dioxide and 10% hydrogen. The rubber lids were self-sealing and remained air-tight after piercing with a fine bore needle. All materials were de-gassed and stored under anaerobic conditions ready for use within this chamber. The faeces of each donor were processed separately and, in each case, experiments were set up in duplicate. Each sample was homogenised in sterile, de-gassed PBS buffer to form a faecal slurry. Other materials included sterile, de-gassed 119 DSMZ culture medium, a planktonic growth of Methanibrevibacter smithii in culture medium, and virus in culture medium. The in vitro colon model vessels were filled within the confines of the anaerobic chamber with either faecal slurry and culture medium, or faecal slurry, Methanibrevibacter smithii and culture medium, as shown in Table 1. The rubber lids were applied and the vessels were sealed. Thereafter, the seal was pierced with a 25G needle attached at all times to a gas line carrying a mixture of 90% hydrogen and 10% carbon dioxide at 1 bar above atmospheric pressure and gas was delivered to each vessel for a period of 45 seconds before the needle was withdrawn. Thus, each air-tight vessel in the in vitro colon model contained 20.2ml of liquid under a hydrogen-rich, anoxic gas mixture. The vessels were incubated at 37°C for 24 hours after which 1.0ml of gas was withdrawn via a gas-tight Hamilton syringe for detection of methane to ensure all vessels contained viable growths of archaea. Using a syringe and 25G needle inserted through the rubber lid of each sealed vessel, either 1.8ml of culture medium or 1.8ml of virus in culture medium were added, as shown in Table 1. The vessels were incubated further for 48 hours at 37°C, after which 1.0ml of gas was withdrawn and transferred into labelled and sealed 10ml Hungate tubes ready for analysis. Table 1 Culture medium M. smithii in culture medium Homogenised faeces initial liquid volume Virus in cuture medium Culture medium Final liquid volume (ml) (ml) (ml) (ml) (ml) (ml) (ml) Faeces Only control 19.2 0 1 20.2 0 1.8 22 faeces + M. smiths control 18.1 1.1 1 20.2 0 1.8 22 faeces + M. smiths + Virus 18.1 1.1 1 20.2 1.8 0 22 Setup at start of 24 hours incubation period Set up at start of 48 hours incubation period Table 1: Initial in vitro colon model liquid contents at the starts of the 24 hour and 48 hour incubation periods. Using a gas-tight Hamilton syringe, 200pl of gas were taken from each labelled Hungate tube and analysed separately via gas chromatography (GC). By subtracting the GC reading for methane generated in the Faeces Only control for each faecal sample, the contribution made by the Methanibrevibacter smithii spike could be elucidated. Having corrected for methane in the Faeces Only control, the GC readings for Faeces + Methanibrevibacter smithii could be compared with the GC readings for Faeces + Methanibrevibacter smithii + Virus, thereby determining the impact of virus on methane emissions in the in vitro colon model. The data in Table 2 show that each faecal sample cultured in the absence of spiked Methanibrevibacter smithii generated detectable levels of methane. This indicates that each of the three faecal samples were endowed with intrinsic populations of methanogenic archaea and, by inference, the human donors of these faeces carry methanogenic archaea in their gastrointestinal tracts. The faeces of Donor 1 and Donor 2 displayed the highest and lowest innate ability to generate methane, respectively. As shown in Table 2, the presence of virus reduced the average GC reading for each of the donor faecal samples. Having corrected for methane emission caused by intrinsic populations of archaea in the faecal samples, it can be seen that the presence of virus caused an average reduction in methane emission of between 12.16% and 26.13% under the conditions of the experiment. It will be appreciated that the in vitro colon model used in this experiment is a representation of the anatomical and physiological makeup of the human colon in which ingesta transit times of up to 72 hours are considered normal. In constipation-predominant irritable bowel syndrome (C-IBS), colon transit times of over 100 hours are commonly experienced. It will be further appreciated, therefore, that the benefit imparted by virus on methane emission in vivo in the human colon may be far greater that that demonstrated in the in vitro colon model over an incubation period of only 48 hours. Furthermore, the experiment depicts a scenario in which a naive colon is provided with virus for the first time leading to an initial infection cycle and lysis of the target archaea. In the event of repeated daily dosing with virus, as may be appropriate for a patient with C-IBS, the contribution of infection cycles already established from previous doses would give rise to a more comprehensive methane mitigation effect. Table 2 GC reading at experiment end Faeces Only Faeces + M. smith!! Faeces + M. smith!! + Virus GC reading due to M. smith!! spike in Faeces + M. smith!! GC reading due to M. smith!! spike in ; Faeces + M smithii + i Virus Difference in GC reading due to virus Percentage reduction in GC reading due to virus A \ B C B-A C-A (B-AHGA) ((B-AHC-A)) / (B-A) ; Replicate 1 965.02 \ 1135.82 1365.34 170.8 I 400.32 -229.52 -134.38% Donor 1; Replicate 2 1215.97 \ 1621.78 1322.15 405.81 106.18 I 299.63 73.84% ; Average 1090.495 ] 1378.8 1343.745 288.305 j 253.25 35.055 12.16% ; Replicate 1 566.07 \ 2247.04 1941.84 1680.97 i 1375.77 i 305.2 18.16% J Donor 2 Replicate 2 427.94 1962.04 1427.05 1534.1 i 999.11 534.99 34.87% j ^Average 497,005 \ 2104.54 1684.445 1607.535 1187.44 i 420.095 26.13% Replicate 1 1047.38 | 1911.93 1205.74 864.55 158.36 i 706.19 81.68% 1 Donor 3; Replicate 2 622.72 \ 2464.23 2758.8 1841.51 i 2136.08 I -294.57 -16.00% j Average 835.05 2188.08 1982.27 1353.03 | 1147.22 205.81 15.21% j Table 2: Gas chromatography readings formethane at the end of the experiment and analysis of the generated data NUMBERED EMBODIMENTS OF THE DISCLOSURE 1. A virus capable of inhibiting the formation of methane in vivo in the gastrointestinal tract of a human for use in a method of reducing the production of methane in a human subject, the method comprising administering the virus to the subject. 2. A pharmaceutical composition comprising a virus capable of reducing the formation of methane in vivo in the human gastrointestinal tract. 3. The pharmaceutical composition according to embodiment 2, in the form of a liquid, syrup, capsule, tablet, bead, granule, pellet, lozenge, pill or suppository. 4. The pharmaceutical composition according to embodiment 3, in the form of a tablet. 5. The pharmaceutical composition according to embodiment 4, wherein the tablet is coated with an enteric coating, preferably wherein the tablet is encapsulated with an enteric coating. 6. The pharmaceutical composition of any of embodiments 2-5, wherein the pharmaceutical composition is configured to location-specific release the virus to the human. 7. The pharmaceutical composition of any of embodiments 2-6 for use in a method of reducing the production of methane in a human subject, the method comprising administering the composition to the subject. 8. A method of reducing the production of methane in a human subject, comprising administering to the subject a virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract. 9. The substance for use according to embodiment 1, the pharmaceutical composition for use according to embodiment 7, or the method according to embodiment 8, wherein the human has irritable bowel syndrome. 10. The substance for use, pharmaceutical composition for use or method according to embodiment 9, wherein the irritable bowel syndrome is constipation-predominant irritable bowel syndrome. 11. The virus for use, pharmaceutical composition for use or method of any preceding embodiment, wherein the administration is oral administration or rectal administration, preferably oral administration. 12. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method according to any preceding embodiment, wherein the virus inhibits the metabolic pathway of methane production in the human gastrointestinal tract. 13. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method according to any preceding embodiment, wherein the virus is an inhibitor of methanogens, preferably an inhibitor of methanogens in the Methanobrevibacter genus. 14. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method according to any preceding embodiment, wherein the virus is an inhibitor of Methanobrevibacter smithii. 15. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method according to any preceding embodiment, wherein the virus is a virus which targets metabolic processes involved in methanogenesis. 16. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method according to any preceding embodiment, wherein the virus is stabilised. 17. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method for use according to embodiment 16, wherein the virus is stabilised by immobilisation to a substrate. 18. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method according to embodiment 16 or 17, wherein the virus is immobilised via its head. 19. The pharmaceutical composition, or pharmaceutical composition for use according to any preceding embodiment, wherein the composition further comprises at least one additional virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract of a human. 20. The virus for use, pharmaceutical composition for use or method according to any preceding embodiment, wherein the method further comprises administering at least one additional virus capable of inhibiting the production of methane in vivo in the gastrointestinal tract of a human. 21. The pharmaceutical composition, or pharmaceutical composition for use according to any preceding embodiment, wherein the composition further comprises at least one additional active substance alleviates the symptoms of irritable bowel syndrome. 22. The virus for use, pharmaceutical composition for use or method according to any preceding embodiment, wherein the method further comprises administering at least one additional active substance alleviates the symptoms of irritable bowel syndrome. 23. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method for use according to embodiment 21 or 22 wherein the additional active substance is an antispasmodic. 24. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method for use according to embodiment 23, wherein the antispasmodic comprises hyoscine or a pharmaceutically acceptable salt thereof. 25. The virus for use, pharmaceutical composition, pharmaceutical composition for use or method according to embodiment 24, wherein the viruses are stabilised. The foregoing disclosure provides exemplary embodiments of the invention and is not intended to be limiting. It will be appreciated that various other modifications and variations of the invention are also possible.