KR102011965B1 - Lytic bacteriophage specific for klebsiella genus resistant to antibiotics - Google Patents

Lytic bacteriophage specific for klebsiella genus resistant to antibiotics Download PDF

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KR102011965B1
KR102011965B1 KR1020170077540A KR20170077540A KR102011965B1 KR 102011965 B1 KR102011965 B1 KR 102011965B1 KR 1020170077540 A KR1020170077540 A KR 1020170077540A KR 20170077540 A KR20170077540 A KR 20170077540A KR 102011965 B1 KR102011965 B1 KR 102011965B1
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용동은
전종수
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Abstract

본 발명은 항생제에 대한 내성을 갖는 클렙시엘라(Klebsiella)속 균을 용균시키는 박테리오파지에 관한 것으로, 구체적으로는 서열번호 2로 표시되는 유전체를 포함하는 YMC15/09/U2874_KPN_BP 박테리오파지 (기탁번호: [KCTC18571P])를 제공한다.
본 발명에서 제공하는 항생제 내성 클렙시엘라속 균에 대하여 특이적 사멸능을 가지므로, 항생제 내성 클렙시엘라속 균에 의해 유발되는 질환의 예방 및 치료 목적으로 활용할 수 있다.
The present invention relates to a bacteriophage that lysates the genus Klebsiella , which is resistant to antibiotics. Specifically, the present invention relates to YMC15 / 09 / U2874_KPN_BP bacteriophage (Accession No .: [KCTC18571P]. ])
Since it has a specific killing ability against the antibiotic resistant Klebsiella spp. Provided by the present invention, it can be used for the prevention and treatment of diseases caused by the antibiotic-resistant Klebsiella spp.

Description

항생제 내성을 갖는 클렙시엘라(Klebsiella)속 균을 용균하는 박테리오파지{LYTIC BACTERIOPHAGE SPECIFIC FOR KLEBSIELLA GENUS RESISTANT TO ANTIBIOTICS}LYTIC BACTERIOPHAGE SPECIFIC FOR KLEBSIELLA GENUS RESISTANT TO ANTIBIOTICS for lysing Klebsiella spp. With antibiotic resistance

본 발명은 항생제에 대한 내성을 갖는 클렙시엘라(Klebsiella)속 균을 용균시키는 박테리오파지에 관한 것이다.The present invention relates to bacteriophages that lyse the genus Klebsiella , which is resistant to antibiotics.

클렙시엘라(Klebsiella)속 균에 해당하는 클렙시엘라 뉴모니아(Klebsiella pneumoniae)는 그람 음성의 피막을 가진 혐기성 세균으로 입, 피부, 장 등의 정상세균총에서 발견된다. 병원 밖 클렙시엘라 세균에 의해 유발되는 가장 흔한 감염질환은 폐렴이 있으며, 전형적으로 기관지폐렴 및 기관지염의 형태로 나타난다. 클렙시엘라 뉴모니아는 감염 및 출혈을 통해 인간 폐를 파괴할 수 있고, 때로는 점액성 객담을 생성하기도 한다. 상기 세균은 전형적으로 구강 인두에 대량으로 서식하는 미생물 흡입에 의해 기도로 들어가 감염을 유발하는 것으로 알려져 있다.Keulrep when Ella (Klebsiella) Oh keulrep when Ella pneumoniae for the Species (Klebsiella pneumoniae) are found in the normal flora of the mouth, skin, intestinal anaerobic bacteria such as with a coat of Gram-negative. The most common infectious diseases caused by out-of-hospital Klebsiella bacteria are pneumonia, typically in the form of bronchial pneumonia and bronchitis. Klebsiella pneumoniae can destroy human lungs through infection and bleeding, sometimes producing mucus sputum. The bacteria are known to enter the airways by inhalation of microorganisms, typically in large quantities in the oropharyngeal pharynx, causing infection.

상기 클렙시엘라속 균의 감염은 대부분 면역력이 약한 사람에게서 두드러지게 나타나며, 항균 치료를 수행하더라도 약 50%의 높은 사망률을 나타내고 있다. 특히, 클렙시엘라 뉴모니아는 구강 등의 흡입 이외에도 비뇨기관, 쓸개관 및 수술에 의한 상처 부위에서도 감염을 유발할 수 있다. 최근, 클렙시엘라 뉴모니아가 병원 내 감염에 있어서 매우 중요한 병원균으로 인식되고 있다.Infections of the genus Klebsiella are most pronounced in people with weak immunity, and show high mortality rates of about 50% even when antibacterial treatment is performed. In particular, Klebsiella pneumoniae can cause infection in the urinary tract, gallbladder and wound site by surgery in addition to inhalation of the oral cavity. Recently, Klebsiella pneumoniae has been recognized as a very important pathogen for infection in hospitals.

항생제 오남용 및 이로 인한 내성균 출현 등으로 대표되는 기존 합성 항생제의 문제점이 세계적으로 크게 이슈화되어 있는 상황에서 이에 대한 해결책을 제시해 줄 수 있는 대상으로 주목을 받고 있는 것이 바로 박테리오파지(Bacteriophage) 및 박테리오파지 유래의 리신(Lysin) 단백질이다. 박테리오파지 및 리신 단백질은 기존 항생 물질과는 완전히 다른 계열이라 할 수 있으며 이에 따라 전혀 다른 항균(antibacterial) 작용 기작(mode of action)을 갖고 있다. 따라서 기존 항생제의 사용에서 나타나던 여러 부작용(side effect)이나 문제점을 개선할 수 있을 것으로 기대를 모으고 있다.In the situation where the problem of the existing synthetic antibiotics, which is represented by the abuse of antibiotics and the emergence of resistant bacteria, has become a major issue in the world, it is attracting attention as an object that can provide a solution to this problem. Lysine derived from bacteriophage and bacteriophage (Lysin) protein. Bacteriophage and lysine proteins are a completely different family of existing antibiotics and thus have a completely different antibacterial mode of action. Therefore, it is expected that the side effects or problems of the existing antibiotics could be improved.

박테리오파지는 박테리아를 감염시킬 수 있으며 보통 파지(phage)라고 줄여서 부르기도 한다. 박테리오파지는 핵산으로 이루어진 유전물질 중심부를 단백질 외피가 싸고 있는 단순한 구조의 유기체이며, 핵산은 단일 사슬이거나 이중 사슬인 DNA 또는 RNA로 되어있다. 박테리오파지는 생존에 숙주(host)가 반드시 필요하며, 모든 박테리아에는 특정 박테리오파지가 존재한다고 알려져 있다. 박테리오파지는 박테리아의 세포벽(cell wall)의 펩티도글리칸(peptidoglycan) 층(layer)을 공격하여 세포벽을 파괴함으로써 박테리아를 사멸시킬 수 있다. 박테리오파지는 1915년 영국의 세균학자 Twort와 1917년 프랑스의 dHerelle에 의해 독립적으로 규명되었으며 세균을 잡아먹는다는 뜻에서 박테리오파지라고 명명되었다. 박테리오파지의 항박테리아 활성(antibacterial activity) 때문에 발견 직후부터 인체와 동물의 질병 치료에 사용되었다. 그러나 Flemming에 의해 페니실린이 발견된 이후, 계속된 다양한 항생제의 등장 및 보급화로 인하여 서구에서는 관심이 점차 줄어들게 되었다. 그러나 러시아와 독일 등의 동구권 나라들은 박테리오파지 연구를 계속 해왔으며 관련하여 다수의 제품들이 산업화된 바도 있다. 하지만, 2000년대에 이르러 항생제 내성균 문제가 부각되면서 서구에서도 다시 박테리오파지에 대하여 관심을 갖게 되었으며 그 후 약 7~8년이 흐른 최근, 산업화 사례들이 속속 보고되고 있다. 즉, 박테리오파지가 세계적으로 새롭게 재조명되기 시작한 시기는 2000년대 초반으로, 실질적 산업화 노력이 약 7 ~ 8 여년 정도 진행된 신규한 분야로서, 생명공학기술의 발전과 맞물려 최근 매우 활발히 관련 개발이 진행되고 있는 분야라 할 수 있다.Bacteriophages can infect bacteria and are often called abbreviated phages. Bacteriophages are organisms with a simple structure in which a protein envelope is wrapped around a core of a genetic material consisting of nucleic acids, and nucleic acids are made of DNA or RNA, which are single or double chains. Bacteriophages require a host to survive, and all bacteria are known to have a specific bacteriophage. Bacteriophages can kill bacteria by attacking the peptidoglycan layer of the cell wall of the bacteria and destroying the cell wall. The bacteriophage was independently identified by British bacteriologist Twort in 1915 and dHerelle in France in 1917 and was named bacteriophage in the sense of eating bacteria. Because of the antibacterial activity of bacteriophage, it has been used for the treatment of diseases in humans and animals right after its discovery. However, after the discovery of penicillin by Flemming, interest has gradually diminished in the West due to the continued emergence and spread of various antibiotics. However, Eastern bloc countries such as Russia and Germany have continued to study bacteriophages, and many products have been industrialized. However, with the emergence of antibiotic-resistant bacteria in the 2000s, the West became interested in bacteriophages again, and about seven to eight years later, recent industrialization cases have been reported. In other words, the new era of bacteriophages began to be re-examined globally in the early 2000s, with the actual industrialization efforts taking place for about 7 to 8 years. It can be said.

박테리오파지의 가장 큰 특징으로는, 감염성 박테리아 속에 침투한 다음 박테리아의 세포벽을 파괴하여 박테리아의 사멸을 유도한다는 것이며, 이러한 박테리오파지에 의한 세포 사멸의 기작은 세균의 세포벽 합성을 방해하는 방식의 기존 합성 항생제의 기작과는 완전히 다르다. 따라서 기존 합성 항생제에 대한 감수성에 관계없이 자신의 항균 활성을 발휘할 수 있다. 이로 인하여 특히 기존 항생제에 대하여 이미 내성을 획득한 내성균에 대해서도 항균 효과가 있다. 또한, 박테리아에 대해서는 매우 특이적인 항균 활성을 가지고 있기 때문에 인간을 포함한 동물을 구성하는 세포인 진핵세포(eukaryotic cell)에는 영향을 주지 않는다는 장점을 갖고 있다.The most distinctive feature of bacteriophages is that they penetrate into infectious bacteria and then destroy the cell walls of the bacteria, leading to the killing of bacteria. The mechanism of cell death by these bacteriophages prevents the bacterial cell wall synthesis. It is completely different from the mechanism. Therefore, they can exert their antimicrobial activity regardless of their sensitivity to existing synthetic antibiotics. Because of this, there is an antimicrobial effect, especially against resistant bacteria that have already obtained resistance to existing antibiotics. In addition, since bacteria have very specific antimicrobial activity, they do not affect eukaryotic cells, which are cells constituting animals including humans.

본 발명의 일 목적은 항생제 내성 클렙시엘라속 균에 대하여 특이적인 감염 및 세포 사멸 능력을 갖는 신규한 박테리오파지를 제공하는 것이다.One object of the present invention is to provide a novel bacteriophage having specific infection and cell killing ability against antibiotic resistant Klebsiella spp.

본 발명의 다른 목적은 클렙시엘라속 균에 대하여 특이적인 세포 사멸 능력을 갖는 신규한 박테리오파지를 유효성분으로 포함하여, 상기 클렙시엘라속 균에 의해 유발되는 질환의 예방 또는 치료용 약학 조성물 및 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention comprises a novel bacteriophage having a specific cell killing ability against the genus Klebsiella bacteria as an active ingredient, the pharmaceutical composition and improvement for the prevention or treatment of diseases caused by the Klebsiella spp. It is to provide a food composition for.

본 발명의 또 다른 목적은 본 발명에 따른 상기 박테리오파지를 포함하는 항생제 및 소독제를 제공하는 것이다.Still another object of the present invention is to provide an antibiotic and a disinfectant comprising the bacteriophage according to the present invention.

그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

본 발명의 발명자들은 항생제 내성 세균 감염증 치료의 대안 물질로 기존의 화학 용법 제제를 보완할 수 있는 박테리오파지를 검토하던 중 항생제 내성 클렙시엘라(Klebsiella)속 균을 선택적으로 사멸시킬 수 있는 박테리오파지를 분리하고, 분리된 박테리오파지의 형태적 및 유전적 특성을 분석하여 이를 타 박테리오파지와 구별하여 특정 지을 수 있는 유전체(genome)의 유전자 서열을 제공하며, 더 나아가 항생제 내성 클렙시엘라속 균에 특이적 사멸능을 갖는 분리된 박테리오파지를 이용하여 상기 항생제 내성 클렙시엘라속 균에 의해 유발되는 질환의 예방 및 치료 목적으로 이용함으로써 본 발명을 완성하였다.The inventors of the present invention and remove the bacteriophage capable of selectively killing the spp antibiotic resistance keulrep when Ella (Klebsiella) While reviewing a bacteriophage that can complement existing chemical usage agents as an alternative material of the antibiotic-resistant bacterial infection therapy By analyzing the morphological and genetic characteristics of the isolated bacteriophages, they can be distinguished from other bacteriophages and provide gene sequences that can be specified. Furthermore, they have specific killing ability against antibiotic-resistant Klebsiella spp. The present invention has been completed by using the isolated bacteriophage having the purpose of preventing and treating diseases caused by the antibiotic resistant Klebsiella spp.

구체적으로, 본 발명자들은 항생제 내성 클렙시엘라속 균을 선택적으로 사멸시키기 위해 예의 노력한 결과, 병원체로부터 카바페넴 내성을 갖는 클렙시엘라 뉴모니아(Klebsiella pneumoniae)를 분리하였고, 상기 카바페넴 내성 클렙시엘라 뉴모니아를 특이적으로 사멸시킬 수 있는 신규한 박테리오파지를 선별하여 이를 'YMC15/09/U2874_KPN_BP'로 명명하였다. 이렇게 선별된 박테리오파지 YMC15/09/U2874_KPN_BP를 2017년 5월 11일자로 한국생명공학연구원 미생물자원센터 (기탁번호: [KCTC18571P])에 기탁하였다.Specifically, the present inventors have made efforts to selectively kill antibiotic resistant Klebsiella spp., And as a result, isolated Klebsiella pneumoniae having carbapenem resistance from the pathogen, and the carbapenem resistant Klebsi A novel bacteriophage capable of specifically killing Ella pneumoniae was selected and named as 'YMC15 / 09 / U2874_KPN_BP'. The screened bacteriophage YMC15 / 09 / U2874_KPN_BP was deposited on May 11, 2017 at the Korea Institute of Bioscience and Biotechnology Microbial Resource Center (Accession No .: [KCTC18571P]).

본 발명의 일 구현 예에 따르면 항생제 내성 클렙시엘라(Klebsiella)속 균에 대하여 선택적 사멸능을 갖는 박테리오파지를 제공한다. According to one embodiment of the present invention provides antibiotic resistance keulrep when bacteriophage having selective killing ability against spp Ella (Klebsiella).

본 발명에서 상기 클렙시엘라(Klebsiella)속 균은 장내세균과의 한 속으로, 협막을 지니며 점액을 생산하고, 탄소원으로서 구연산염을 이용하는 균으로, 자연계에 널리 존재하며 사람의 호흡기, 장관 및 비뇨기에서 검출된다. 일반적으로 상기 균은 비병원성이지만 다양한 질병의 2차 감염과 폐렴 등의 질환의 원인이 될 수 있다. In the present invention, the genus Klebsiella is a genus of intestinal bacteria, has mucous membranes, produces mucus, and uses citrate as a carbon source, and is widely present in nature and is widely used in human respiratory, intestinal and urinary organs. Is detected. Generally, the bacterium is non-pathogenic but may be a cause of diseases such as secondary infection and pneumonia of various diseases.

본 발명에서, 상기 클렙시엘라속 균은 클렙시엘라 뉴모니아(Klebsiella pneumoniae), 클렙시엘라 옥시토카(Klebsiella oxytoca), 클렙시엘라 플란티콜라(Klebsiella planticola) 및 클렙시엘라 테리게나(Klebsiella terrigena)로 구성된 군으로부터 선택되는 어느 1종 이상일 수 있으며, 바람직하게는 클렙시엘라 뉴모니아(Klebsiella pneumoniae)일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the genus Klebsiella pneumoniae ( Klebsiella pneumoniae ), Klebsiella oxytoca ( Klebsiella) oxytoca ), Klebsiella planticola and Klebsiella terrigena may be any one or more selected from the group consisting of, preferably Klebsiella pneumoniae May be, but is not limited thereto.

또한, 본 발명에서 상기 클렙시엘라 뉴모니아(Klebsiella pneumoniae)는 간균으로도 불리우며, 아종으로 뉴모니아(Pneumoniae), 아자니아(Azaenae) 및 리노스틸레로마티스(Rhinoscleromatis)가 존재하며, 상기 균은 급성폐렴, 취비증, 비경종증을 유발할 수 있다. 또한, 항생물질에 내성이 존재하고, 건조하지 않는 경우 실온에서 수개월 동안 생존할 수 있다. In addition, the Klebsiella pneumatic ( Klebsiella) in the present invention pneumoniae ) is also called bacilli, and subspecies include Pneumoniae , Azaenae and Rhinoscleromatis , which can cause acute pneumonia, numbness , and rhinomatosis . . In addition, antibiotics are resistant and can survive for months at room temperature if they are not dry.

본 발명에서 상기 "항생제 내성"은 특정 항생제에 내성을 보여 약효가 듣지 않는 것을 의미하며, 본 발명의 목적상 상기 항생제는 카바페넴(Carbapenem)의 구조를 갖는 항생제일 수 있다. 구체적으로, 아미카신(Amicacin), 앰피실린(Ampicillin), 엠피실린/설벡탐(Ampicillin/Sulbactam), 아즈트레오남(Aztreonam), 세즈타지딤(Ceftazidime), 세파졸린(Cefazolin), 에르타페넴(Ertapenem), 세페핌(Cefepime), 세폭시틴(Cefoxitin), 세포탁심(Cefotaxime), 젠타마이신(Gentamicine), 레보플록세신(Levoflocacin), 메로페넴(Meropenem), 피페라실린/타조박탐(Piperacillin/Tazobactam), 코트리목사(Cortrimoxa), 및 티게틸린(Tigecyline)으로 구성된 군으로부터 선택되는 1종 이상일 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 목적상 상기 클렙시엘라 뉴모니아는 항생제 내성을 갖는 것일 수 있고, 상기 항생제 내성은 상기 카바페넴을 분해하여 효과의 발휘를 억제하는 카바페넴아제 효소(carbapenemase)를 생산함으로써 발생될 수 있다.In the present invention, the "antibiotic resistance" means that the drug is not effective because it shows resistance to a specific antibiotic, the antibiotic may be an antibiotic having a structure of carbapenem (Carbapenem) for the purpose of the present invention. Specifically, Amicacin, Ampicillin, Ampicillin / Sulbactam, Aztreonam, Ceftazidime, Cefazolin, Ertafenem (Ertapenem), Cefepime, Cefoxitin, Cefotaxime, Gentamycin, Gentamicine, Levoflocacin, Meropenem, Piperacillin / Tazobactam (Piperacillin) / Tazobactam), Cortrimoxa, and Tigecyline may be one or more selected from the group consisting of, but is not limited thereto. For the purposes of the present invention, the Klebsiella pneumoniae may have antibiotic resistance, and the antibiotic resistance may be generated by producing a carbapenemase which decomposes the carbapenem and inhibits the exertion of the effect. .

본 발명에서 상기 “박테리오파지”는 세균을 숙주세포로 하는 바이러스 일군의 총칭으로, 숙주에 감염된 후 증식하여 자손 파지를 방출하는 용균성을 갖는 회로 또는 숙주 염색체와 공존한 상태에서 숙주는 생존하고, 파지 DNA는 복제하는 회로를 갖는다. In the present invention, the "bacteriophage" is a generic term for a group of viruses including bacteria as host cells, and the host survives and coexists with a circuit or host chromosome having a lytic ability to proliferate after infection with the host and release progeny phage. DNA has a circuit that replicates.

본 발명에서 제공하는 상기 박테리오파지는 서열번호 2로 표시되는 유전체를 포함하는 것일 수 있는데, 상기 서열번호 2는 상기 박테리오파지의 ORF(Open reading frame)49로, 상기 클렙시엘라속 균을 용균하는 기능을 수행하는 엔돌리신(endolysin)을 코딩하는 유전체를 표시하는 염기 서열일 수 있으며, 본 발명의 박테리오파지의 특징적 서열에 해당한다. The bacteriophage provided by the present invention may include a genome represented by SEQ ID NO: 2, wherein SEQ ID NO: 2 is an ORF (Open reading frame) 49 of the bacteriophage, which functions to lyse the genus Klebsiella spp. It may be a base sequence that represents the genome encoding endolisin to perform, and corresponds to the characteristic sequence of the bacteriophage of the present invention.

보다 바람직하게는, 본 발명에서 제공하는 상기 박테리오파지는 서열번호 1로 표시되는 유전체로 이루어지는 것일 수 있다.More preferably, the bacteriophage provided by the present invention may be composed of a genome represented by SEQ ID NO: 1.

또한, 본 발명에서 상기 박테리오파지는 시포비리데(siphoviridae)에 속하는 박테리오파지일 수 있다. In the present invention, the bacteriophage may be a bacteriophage belonging to sipoviriridae (siphoviridae).

단, 본 발명에서 상기 “시포비리데(siphoviridae)”는 박테리오파지를 전자현미경을 통한 형태 관찰에 의해 분류 및 동정하는 방법에 의해 분류된 것으로, 수축성이 없는 수축성이 없는 긴 꼬리(a long non-contractile tail)를 갖는 복합형의 형태를 나타낸 것일 수 있다.However, in the present invention, the "siphoviridae" is classified by a method of classifying and identifying bacteriophages by morphological observation through an electron microscope, and a long non-contractile without contractility. It may represent a complex type having a tail).

본 발명의 다른 구현 예에 따르면, 본 발명에 따른 박테리오파지 YMC15/09/U2874_KPN_BP를 유효성분으로 포함하는 항생제 내성 클렙시엘라속 균 유발성 질환의 예방 또는 치료용 약학 조성물을 제공한다.According to another embodiment of the present invention, a bacteriophage YMC15 / 09 / U2874_KPN_BP according to the present invention provides a pharmaceutical composition for preventing or treating antibiotic-resistant Klebsiella spp.-inducing disease.

본 발명의 약학 조성물은 1 × 103 내지 1 × 1010 pfu/㎖의 박테리오파지를 포함하며, 바람직하게는 1 × 106 내지 1 × 109 pfu/㎖의 박테리오파지를 포함할 수 있다.The pharmaceutical composition of the present invention comprises 1 × 10 3 to 1 × 10 10 pfu / ml of bacteriophages, preferably 1 × 10 6 to 1 × 10 9 pfu / ml of bacteriophages.

본 발명의 약학 조성물에 포함되는 박테리오파지 YMC15/09/U2874_KPN_BP는 상술한 바와 같이, 항생제 내성 클렙시엘라속 균, 바람직하게는 카바페넴 내성 클렙시엘라속, 보다 바람직하게는 카바페넴 내성 클렙시엘라 뉴모니아를 특이적으로 사멸시킬 수 있는 용균능 및 흡착능이 존재하므로, 본 발명의 약학 조성물을 사용하는 경우 상기 항생제 내성 클렙시엘라속 균을 용균 및 사멸시켜 인체 내에서 상기 항생제 내성 클렙시엘라 속 균의 감염으로 인하여 유발되는 다양한 질환을 효과적으로 예방 또는 치료할 수 있다. As described above, the bacteriophage YMC15 / 09 / U2874_KPN_BP included in the pharmaceutical composition of the present invention is antibiotic-resistant Klebsiella spp., Preferably Carbapenem-resistant Klebsiella spp., More preferably Carbapenem-resistant Klebsiella pneumoniae Since there is a lytic ability and adsorption capacity capable of killing moniae specifically, when using the pharmaceutical composition of the present invention, the antibiotic-resistant Klebsiella spp. Lysates and kills the antibiotic-resistant Klebsiella spp. Various diseases caused by bacterial infection can be effectively prevented or treated.

본 발명에서 상기 클렙시엘라속 균 유발성 질환은 패혈증, 폐렴 및 폐기종으로 이루어진 군에서 선택되는 어느 하나일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the Klebsiella spp. Inducing disease may be any one selected from the group consisting of sepsis, pneumonia, and emphysema, but is not limited thereto.

본 명세서에서 사용된 '치료'라는 용어는 (ⅰ) 클렙시엘라속 균 에 의해 유발된 질환의 예방; (ⅱ) 클렙시엘라속 균 에 의해 유발된 질환의 억제; 및 (ⅲ) 클렙시엘라속 균 에 의해 유발된 질환의 경감을 의미한다.The term 'treatment' as used herein refers to (i) prevention of diseases caused by the genus Klebsiella; (Ii) suppression of diseases caused by Klebsiella spp .; And (iii) alleviation of diseases caused by the genus Klebsiella.

본 발명에서 상기 약학 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be characterized in that the capsule, tablets, granules, injections, ointments, powder or beverage form, the pharmaceutical composition may be characterized in that it is intended for humans.

본 발명에서 상기 약학 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.In the present invention, the pharmaceutical composition is not limited thereto, but may be used in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, capsules, tablets, and aqueous suspensions, respectively, according to conventional methods. Can be. The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be used as oral administration binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc. In the case of injections, buffers, preservatives, analgesic Topical agents, solubilizers, isotonic agents, stabilizers and the like can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives and the like can be used. The formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms. have. And other solutions, suspensions, tablets, capsules, sustained release preparations and the like.

한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항 응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of suitable carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil and the like can be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may further be included.

본 발명에 상기 약학 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition in the present invention is not limited to these, oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Sublingual or rectal. Oral or parenteral release is preferred.

본 발명에서 상기 "비경구"란, 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional and intracranial injection or infusion techniques. The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.

본 발명의 상기 약학 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다. The pharmaceutical composition of the present invention depends on a number of factors, including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination and severity of the particular disease to be prevented or treated, of the specific compound employed. The dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, extent of disease, drug form, route of administration, and duration, and may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg / kg per day. Or 0.001 to 50 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions.

본 발명의 또 다른 구현 예에 따르면, 본 발명에 따른 박테리오파지 YMC15/09/U2874_KPN_BP를 유효성분으로 포함하는 항생제 내성 클렙시엘라속 균 유발성 질환의 예방 또는 개선용 식품 조성물을 제공한다.According to another embodiment of the present invention, a bacteriophage YMC15 / 09 / U2874_KPN_BP according to the present invention provides a food composition for preventing or improving antibiotic resistant Klebsiella spp.-inducing disease.

본 발명의 식품 조성물은 1 × 103 내지 1 × 1010 pfu/㎖의 박테리오파지를 포함하며, 바람직하게는 1 × 106 내지 1 × 109 pfu/㎖의 박테리오파지를 포함할 수 있다.The food composition of the present invention comprises 1 × 10 3 to 1 × 10 10 pfu / ml of bacteriophages, and preferably 1 × 10 6 to 1 × 10 9 pfu / ml of bacteriophages.

본 발명의 식품 조성물에 포함되는 박테리오파지 YMC15/09/U2874_KPN_BP는 상술한 바와 같이, 항생제 내성 클렙시엘라속 균, 바람직하게는 카바페넴 내성 클렙시엘라속, 보다 바람직하게는 카바페넴 내성 클렙시엘라 뉴모니아를 특이적으로 사멸시킬 수 있는 용균능 및 흡착능이 존재하므로, 본 발명의 약학 조성물을 사용하는 경우 상기 항생제 내성 클렙시엘라속 균을 용균 및 사멸시켜 인체 내에서 상기 항생제 내성 클렙시엘라 속 균의 감염으로 인하여 유발되는 다양한 질환을 효과적으로 예방 또는 개선할 수 있다.As described above, the bacteriophage YMC15 / 09 / U2874_KPN_BP included in the food composition of the present invention is an antibiotic-resistant Klebsiella spp., Preferably a Carbapenem-resistant Klebsiella spp., More preferably a carbapenem-resistant Klebsiella pneumoniae. Since there is a lytic ability and adsorption capacity capable of killing moniae specifically, when using the pharmaceutical composition of the present invention, the antibiotic-resistant Klebsiella spp. Lysates and kills the antibiotic-resistant Klebsiella spp. Various diseases caused by the bacterial infection can be effectively prevented or improved.

본 발명에서 상기 클렙시엘라속 균 유발성 질환은 패혈증, 폐렴 및 폐기종으로 이루어진 군에서 선택되는 어느 하나인 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the Klebsiella spp. Inducing disease may be any one selected from the group consisting of sepsis, pneumonia, and emphysema, but is not limited thereto.

한편, 본 발명에서, “개선”은 본 발명의 식품 조성물을 이용하여 클렙시엘라속 균의 감염으로 인해 발생한 증상이 호전 또는 이롭게 변경되는 모든 행위라면 제한없이 포함할 수 있다.On the other hand, in the present invention, "improvement" may be used without limitation if all the symptoms improved or beneficially changed symptoms caused by the infection of the genus Klebsiella using the food composition of the present invention.

본 발명의 상기 박테리오파지를 유효성분으로 포함하는 식품 조성물은 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. The food composition comprising the bacteriophage of the present invention as an active ingredient may be prepared in the form of various foods, for example, beverages, gums, teas, vitamin complexes, powders, granules, tablets, capsules, sweets, rice cakes, breads, and the like. have.

본 발명에서 상기 박테리오파지가 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 50%의 비율로 첨가할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when the bacteriophage is included in the food composition, the amount may be added at a ratio of 0.1 to 50% of the total weight, but is not limited thereto.

본 발명에서 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 포함하는 것 외에 특별한 제한점은 없으며, 통상의 음료와 같이 다양한 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 구체적으로, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등) 등일 수 있다. In the present invention, when the food composition is prepared in the form of a beverage, there is no particular limitation other than including the food composition in the ratio indicated, and may include various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. . Specifically, monosaccharides such as glucose, disaccharides such as fructose, sucrose and the like, and common sugars such as polysaccharides, dextrins and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol are used as natural carbohydrates. It may include. The flavourant may be a natural flavourant (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.), synthetic flavors (saccharin, aspartame, etc.).

본 발명에서, 그 외 본 발명의 상기 식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 포함할 수 있다.In the present invention, the above food composition of the present invention is a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids , Protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.

본 발명에서 상기 성분은 독립적 또는 조합하여 사용할 수 있다. 상기 첨가제의 비율은 본 발명의 핵심적인 요소에 해당하지 아니하지만, 본 발명의 식품 조성물 100 중량부 당 0.1 내지 약 50 중량부의 범위에서 선택될 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the above components may be used independently or in combination. The ratio of the additive does not correspond to the essential element of the present invention, but may be selected from 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.

본 발명의 또 다른 구현 예는 본 발명에 따른 박테리오파지 YMC15/09/U2874_KPN_BP를 유효성분으로 포함하는 항생제를 제공한다.Another embodiment of the present invention provides an antibiotic comprising bacteriophage YMC15 / 09 / U2874_KPN_BP as an active ingredient according to the present invention.

본 발명에서 상기 항생제는, 대부분의 다른 항생 물질들은 대상체인 균주의 내성이 증가함에 따라 갈수록 사용범위가 줄어들 수 밖에 없는 데에 반하여, 본 발명의 상기 항생제는 상기와 같은 문제점과 무관하게 사용될 수 있으므로 항생제로 사용될 수 있는 수명이 길어질 수 있다.In the present invention, the antibiotics, while most other antibiotics are bound to decrease in use as the resistance of the strain is increased, the antibiotics of the present invention can be used irrespective of the above problems Long lifespans that can be used as antibiotics can be extended.

단, 본 발명에서 상기 "항생제"는 방부제, 살균제 및 항균제를 총칭하는 의미를 나타낸다.However, in the present invention, the "antibiotic" refers to a generic term for preservatives, fungicides and antibacterial agents.

본 발명의 또 다른 구현 예는 본 발명에 따른 박테리오파지 YMC15/09/U2874_KPN_BP를 유효성분으로 포함하는 소독제를 제공한다.Another embodiment of the present invention provides a disinfectant comprising bacteriophage YMC15 / 09 / U2874_KPN_BP as an active ingredient according to the present invention.

본 발명에서 상기 소독제는 항생제 내성 클렙시엘라속 균에 대하여 특이적 사멸능을 갖는 박테리오파지를 유효성분으로 하고 있으므로, 병원에서의 감염을 방지하기 위한 병원 및 보건용 도구 등의 소독제로 유용하게 사용될 수 있고, 일반 생활 소독제, 식품 및 조리 장소 및 설비의 소독제, 축산 산업의 축사 소독제로 유용하게 사용될 수 있다.In the present invention, since the disinfectant is a bacteriophage having specific killing ability against antibiotic resistant Klebsiella spp. As an active ingredient, it can be usefully used as a disinfectant for hospitals and health care tools to prevent infection in hospitals. It can be usefully used as a general household disinfectant, a disinfectant for food and cooking places and facilities, and a livestock disinfectant in the livestock industry.

본 발명에 따른 신규한 박테리오파지는 항생제 내성 클렙시엘라속 균에 대하여 특이적 사멸능을 가지므로, 항생제 내성 클렙시엘라속 균에 의해 유발되는 질환의 예방 및 치료 목적으로 활용할 수 있다.Since the novel bacteriophage according to the present invention has a specific killing ability against antibiotic-resistant Klebsiella spp., It can be used for the prevention and treatment of diseases caused by antibiotic-resistant Klebsiella spp.

도 1은 본 발명의 일 실시예에 따른 박테리오파지의 전자 현미경 촬영 사진을 나타낸 것이다.
도 2는 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 흡창능을 그래프로 나타낸 것이다.
도 3은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 1단 증식 곡선을 나타낸 것이다.
도 4는 본 발명의 일 실시예에 따른 생체 외에서 박테리오파지의 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균능을 그래프로 나타낸 것이다.
도 5는 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 pH 안정성을 그래프로 나타낸 것이다.
도 6은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 온도 안정성을 그래프로 나타낸 것이다.
도 7은 본 발명의 일 실시예에 따른 항생제 내성을 갖는 클렙시엘라속 균에 대한 용균성 박테리오파지의 전체 유전체 서열 분석 결과를 나타낸 것이다.
1 shows an electron micrograph of a bacteriophage according to an embodiment of the present invention.
Figure 2 is a graph showing the absorption capacity of lytic bacteriophage against the genus Klebsiella bacteria having antibiotic resistance according to an embodiment of the present invention.
Figure 3 shows a one-step proliferation curve of lytic bacteriophage against antibiotics of the genus Klebsiella bacteria having antibiotic resistance according to an embodiment of the present invention.
Figure 4 is a graph showing the lytic ability against the bacteriophage antibiotics Klebsiella genus bacteria in vitro in accordance with an embodiment of the present invention.
5 is a graph showing the pH stability of lytic bacteriophages against Klebsiella spp. Having antibiotic resistance according to an embodiment of the present invention.
6 is a graph showing the temperature stability of lytic bacteriophages against the genus Klebsiella bacteria having antibiotic resistance according to an embodiment of the present invention.
Figure 7 shows the results of the entire genome sequence analysis of lytic bacteriophage against the bacterium of the genus Klebsiella having antibiotic resistance according to an embodiment of the present invention.

이하, 본 발명을 하기의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.

실시예Example

[[ 실시예Example 1] 임상검체 분리 및 항생제 내성 균주 선별 1] Isolation of clinical specimens and selection of antibiotic resistant strains

세브란스 병원 환자들로부터 환자의 분변 내 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 균을 배양하여 분리하였다. 그 뒤, 감수성 결과는 Clinical and Laboratory Standards Institute (CLSI, 2009)를 기준으로 판독하였다. 감수성 시험은 뮬러-힌튼(Mueller-Hinton) 아가를 사용하여 외기 37℃에서 하룻밤 동안 배양하는 CLSI 디스크 확산 시험방법을 사용하였다. 클렙시엘라 뉴모니아 균에 대한 시험 항생제는 아미카신(Amicacin), 앰피실린(Ampicillin), 엠피실린/설벡탐(Ampicillin/Sulbactam), 아즈트레오남(Aztreonam), 세즈타지딤(Ceftazidime), 세파졸린(Cefazolin), 에르타페넴(Ertapenem), 세페핌(Cefepime), 세폭시틴(Cefoxitin), 세포탁심(Cefotaxime), 젠타마이신(Gentamicine), 레보플록사신(Levofloxacin), 메로페넴(Meropenem), 피페라실린/타조박탐(Piperacillin/Tazobactam), 코트리목사(Cortrimoxa), 및 티게틸린(Tigecyline)을 사용하였다. 수집된 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 53개 주의 항생제 내성 프로파일은 하기 표 1에 나타내었다. 단, 하기 표 1에서 S, I 및 R은 항균제에 대한 감수성을 평가한 결과로, 'S'는 민감(Susceptible), 'I'는 중간(Intermediate), 'R'은 내성(Resistant)를 의미한다. Klebsiella pneumoniae bacteria in the feces of patients were isolated from Severance hospital patients. The susceptibility results were then read against the Clinical and Laboratory Standards Institute (CLSI, 2009). The susceptibility test used a CLSI disk diffusion test method which was incubated overnight at 37 ° C. with Mueller-Hinton agar. Test antibiotics for Klebsiella pneumoniae are Amikacin, Ampicillin, Ampicillin / Sulbactam, Aztreonam, Ceftazidime, Cefazoline, Ertapenem, Cefepime, Cefoxitin, Cefaxime, Gentamicine, Levofloxacin, Levofloxacin, Meropenem, Pi Peracillin / Tazobactam (Piperacillin / Tazobactam), Cortrimoxa, and Tigecyline were used. Collected Klebsiella pneumoniae ) 53 resistance antibiotic resistance profiles are shown in Table 1 below. However, in Table 1, S, I and R as a result of evaluating the sensitivity to the antimicrobial agent, 'S' is susceptible (Susceptible), 'I' is Intermediate, 'R' means Resistant do.

숙주 균주Host strain 아미카신Amikacin 엠피실린Empicillin 엠피실린/설벡탐Empicillin / Sulfectam 아즈트레오남Aztreonam 세즈타지딤Seztazidim 세파졸린Sephazoline 에르타페넴Ertafenem 세페핌Cefepime 세폭시틴Sepoxycitin 세포탁심Cell Taksim 젠타마이신Gentamicin 레보플록사신Levofloxacin 메로페넴Meropenem 피페라실린/타조박탐Piperacillin / Tazobactam 코트리목사졸Cotrimok Grad 티게틸린Tigetyline YMC15/11/P488YMC15 / 11 / P488 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) YMC15/11/P546YMC15 / 11 / P546 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC15/09/U2874YMC15 / 09 / U2874 =2 (S)= 2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥16 (R)≥16 (R) 40 (S)40 (S) ≥8 (R)≥8 (R) YMC15/11/N45YMC15 / 11 / N45 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/P756YMC15 / 11 / P756 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≤40 (S)≤40 (S) ≥8 (R)≥8 (R) YMC15/11/N55YMC15 / 11 / N55 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/T741YMC15 / 11 / T741 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≤40 (S)≤40 (S) ≥8 (R)≥8 (R) YMC15/11/U4318YMC15 / 11 / U4318 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≤40 (S)≤40 (S) ≥8 (R)≥8 (R) YMC15/11/P860YMC15 / 11 / P860 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/C1052YMC15 / 11 / C1052 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/10/N12YMC15 / 10 / N12 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/10/U1383YMC15 / 10 / U1383 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≤40 (S)≤40 (S) ≥8 (R)≥8 (R) YMC15/10/P776YMC15 / 10 / P776 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC15/10/N150YMC15 / 10 / N150 ≥16 (R)≥16 (R) YMC15/11/N1073YMC15 / 11 / N1073 ≥16 (R)≥16 (R) YMC15/11/G57YMC15 / 11 / G57 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 25 (S)25 (S) 2 (S)2 (S) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) 4 (I)4 (I) 29 (S)29 (S) ≥128 (R)≥128 (R) ≤20 (S)≤20 (S) ≤0.5 (S)≤0.5 (S) YMC15/11/B4059YMC15 / 11 / B4059 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC15/11/U2284YMC15 / 11 / U2284 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC15/11/N45YMC15 / 11 / N45 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/N53YMC15 / 11 / N53 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/N54YMC15 / 11 / N54 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC15/11/N96YMC15 / 11 / N96 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/N98YMC15 / 11 / N98 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/N101YMC15 / 11 / N101 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/N107YMC15 / 11 / N107 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/N115YMC15 / 11 / N115 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/N137YMC15 / 11 / N137 =2 (S)= 2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≤40 (S)≤40 (S) ≥8 (R)≥8 (R) YMC15/11/R3218YMC15 / 11 / R3218 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC15/11/N154YMC15 / 11 / N154 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC15/11/R3705YMC15 / 11 / R3705 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC15/11/G223YMC15 / 11 / G223 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC15/12/P746YMC15 / 12 / P746 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≤40 (S)≤40 (S) ≥8 (R)≥8 (R) YMC15/12/C910YMC15 / 12 / C910 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/01/R859YMC16 / 01 / R859 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC16/01/N136YMC16 / 01 / N136 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/01/N133YMC16 / 01 / N133 ≤2 (S)≤2 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/01/N141YMC16 / 01 / N141 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/01/N164YMC16 / 01 / N164 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/01/N233YMC16 / 01 / N233 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/01/N359YMC16 / 01 / N359 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/01/R3917YMC16 / 01 / R3917 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/01/R3958YMC16 / 01 / R3958 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥16 (R)≥16 (R) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC16/02/B372YMC16 / 02 / B372 ≤2 (S)≤2 (S) ≥32 (R)≥32 (R) ≥32 (R)≥32 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64≥64 ≥8 (R)≥8 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≤1 (S)≤1 (S) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) ≥320 (R)≥320 (R) ≥8 (R)≥8 (R) YMC16/02/N11YMC16 / 02 / N11 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/02/N162YMC16 / 02 / N162 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/02/N394YMC16 / 02 / N394 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/02/N393YMC16 / 02 / N393 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/02/N499YMC16 / 02 / N499 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/02/N726YMC16 / 02 / N726 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/03/N942YMC16 / 03 / N942 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/04/R1602YMC16 / 04 / R1602 ≤2 (S)≤2 (S) ≥64 (R)≥64 (R) ≥64 (R)≥64 (R) ≥8 (R)≥8 (R) ≥32 (R)≥32 (R) 8 (I)8 (I) ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) ≥128 (R)≥128 (R) YMC16/05/N235YMC16 / 05 / N235 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R) YMC16/05/N151YMC16 / 05 / N151 ≥8 (R)≥8 (R) ≥16 (R)≥16 (R)

상기 표 1에서 보는 바와 같이, 수집된 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 53개 균주는 다양한 카바페넴계 항생제에 대하여 내성을 가지며, 특히 클렙시엘라 뉴모니아 YMC15/09/U2874는 이후 PCR을 수행한 결과 bla KPC 유전자를 갖는 다재내성 균주임을 알 수 있었다.As shown in Table 1 above, the collected 53 Klebsiella pneumoniae strains are resistant to various carbapenem antibiotics, in particular Klebsiella pneumoniae YMC15 / 09 / U2874 is then PCR As a result, it was found that the bacteriostatic strain having the bla KPC gene.

[[ 실시예Example 2] 박테리오파지 검체 수집 2] Bacteriophage Sample Collection

2-1. 파지 은행 구축을 위한 검체 수집2-1. Sample Collection to Build a Phage Bank

세브란스 병원의 하수 처리시설에서 최초 침전지 거친 후 부유물질 및 침사물이 제거된 원수를 확보하였다. 이는 화학 처리 시설 전 단계의 하수로 제한하였다. 수집한 시료에 1L 당 염화나트륨 58g을 첨가한 후 10,000g에서 10분간 원심 분리하여 220nm 밀리포어 필터로 여과하였다. 얻어진 여과액에 폴리에틸렌글리콜(PEG, 분자량 8000)을 10% W/V으로 첨가하고 4에서 12시간 동안 냉장 보관하였다. 12시간 냉장 보관된 여과액을 12,000g에서 20분간 원심 분리하여 침전물을 파지 희석 완충액 (SM 완충액)에 재부유한 뒤, 동일한 양의 클로로포름을 첨가하여 냉동 보관하였다. 이를 3회 반복하여 300mL의 박테리오파지 부유액을 채취하였다.After the initial settling in the sewage treatment facility of Severance Hospital, raw water from which suspended matter and sediment were removed was secured. This was limited to sewage prior to the chemical treatment plant. 58 g of sodium chloride per 1 L was added to the collected sample, and then centrifuged at 10,000 g for 10 minutes and filtered through a 220 nm Millipore filter. Polyethylene glycol (PEG, molecular weight 8000) was added to the obtained filtrate at 10% W / V and refrigerated for 4 to 12 hours. The filtrate stored for 12 hours was centrifuged at 12,000 g for 20 minutes to resuspend the precipitate in phage dilution buffer (SM buffer), and then the same amount of chloroform was added and stored frozen. This was repeated three times to collect a 300 mL bacteriophage suspension.

2-2. 2-2. 용균성Lytic 파지 선별 및  Phage screening and 용균역가Yonggyun titer 측정 Measure

용균성 파지의 분리 정제는 스팟 테스트(Spot Test)법 (Mazzocco A et al. In Bacteriophages, Clokie and Kropinski AM, eds. Humana Press. 2009)으로 실행하였다. 확보된 균주를 맥콘키 한천배지에서 접종 후 외기 35에서 하룻밤 동안 배양하였다. 배양 후, 투명한 플라크 형성을 보고 파지에 감수성인 균주를 선별하였다. 감수성인 균주를 맥콘키 한천 배지에 접종하여 35에서 12시간 동안 배양하였다. 살린 1ml 튜브에 McFarland 0.5 탁도로 각 균주의 현탁액 제조하고 H 탑 아가 (3 ml), 감수성 박테리아 100ul 및 파지 용액 (각각 1ul, 10ul 및 50ul)을 섞어 LB 아가에 도포한 후, 35에서 12시간 동안 배양하였다. 플라크 관찰한 후에 파스퇴르 파이펫으로 플라크를 채취하여 SM 완충 용액에 희석하고, 다시 감수성인 균주 현탁액을 이용하여 3회 반복 정제하였다. 이렇게 얻어진 순수한 박테리오파지는 SM 완충 용액에 희석하고 다시 감수성인 균주 현탁액을 이용하여 3회 반복 정제하였다. 이렇게 얻어진 순수한 박테리오파지는 SM 완충 용액에 희석하여 보관하였다.Isolation and purification of lytic phage was performed by the Spot Test method (Mazzocco A et al. In Bacteriophages, Clokie and Kropinski AM, eds. Humana Press. 2009). The secured strains were incubated overnight at 35 days after inoculation in McConkie agar medium. After incubation, clear plaque formation was observed and strains sensitive to phage were selected. Susceptible strains were inoculated in McConkie Agar medium and incubated for 35 to 12 hours. A suspension of each strain was prepared in a 1 ml tube with McFarland 0.5 turbidity, mixed with H top agar (3 ml), 100 ul of susceptible bacteria and phage solution (1 ul, 10 ul and 50 ul, respectively) and applied to LB agar for 35 to 12 hours. Incubated. After plaque observation, plaques were collected with Pasteur pipettes, diluted in SM buffer solution, and purified three times using susceptible strain suspensions. The pure bacteriophage thus obtained was diluted in SM buffer solution and again purified three times using susceptible strain suspension. The pure bacteriophage thus obtained was stored diluted in SM buffer solution.

실시예 1에서 확인한 항생제 내성 클렙시엘라 뉴모니아(Klebsiella pneumoniae) 53개 균주 각각을 맥콘키 한천배지에서 접종하여 배양한 후, 상기 과정에 의해 정제된 박테리오파지 YMC15/09/U2874_KPN_BP를 도말된 각각의 내성 균주에 5ul로 접종하여 플라그 형성을 확인하고, 역가 범위를 확인하여, 용균성을 하기 표 2에 나타내었다.Each of the 53 antibiotic-resistant Klebsiella pneumoniae strains identified in Example 1 was inoculated and cultured in McConkie agar medium, and then the bacteriophage YMC15 / 09 / U2874_KPN_BP purified by the above procedure was plated. Inoculation with the resistant strain at 5ul to confirm plaque formation, and to check the titer range, the lytic properties are shown in Table 2 below.

단, 상기 표 2에서 + 및 -는 수집된 균주에 대한 플라크 활성을 평가한 것으로, '+'는 투명한 플라크(clear plaque)를 의미하고, '-'는 용균이 일어나지 않은 것을 의미한다.However, in Table 2, + and-are to evaluate the plaque activity for the collected strain, '+' means clear plaque, '-' means that lysis did not occur.

숙주 균주Host strain 용균 여부Lysis 숙주 균주Host strain 용균 여부Lysis YMC15/09/P488YMC15 / 09 / P488 ++ YMC15/11/R3218YMC15 / 11 / R3218 ++ YMC15/09/P546YMC15 / 09 / P546 ++ YMC15/11/N154YMC15 / 11 / N154 ++ YMC15/09/U2874YMC15 / 09 / U2874 ++ YMC15/11/R3705YMC15 / 11 / R3705 ++ YMC15/09/N45YMC15 / 09 / N45 -- YMC15/11/G223YMC15 / 11 / G223 ++ YMC15/09/P756YMC15 / 09 / P756 ++ YMC15/12/P746YMC15 / 12 / P746 ++ YMC15/09/N55YMC15 / 09 / N55 ++ YMC15/12/C910YMC15 / 12 / C910 ++ YMC15/09/T741YMC15 / 09 / T741 ++ YMC16/01/R859YMC16 / 01 / R859 ++ YMC15/09/U4318YMC15 / 09 / U4318 ++ YMC16/01/N136YMC16 / 01 / N136 ++ YMC15/09/P860YMC15 / 09 / P860 ++ YMC16/01/N133YMC16 / 01 / N133 ++ YMC15/09/C1052YMC15 / 09 / C1052 ++ YMC16/01/N141YMC16 / 01 / N141 ++ YMC15/10/N12YMC15 / 10 / N12 ++ YMC16/01/N164YMC16 / 01 / N164 ++ YMC15/10/U1383YMC15 / 10 / U1383 ++ YMC16/01/N233YMC16 / 01 / N233 ++ YMC15/10/P776YMC15 / 10 / P776 ++ YMC16/01/N359YMC16 / 01 / N359 ++ YMC15/10/N150YMC15 / 10 / N150 ++ YMC16/01/R3917YMC16 / 01 / R3917 ++ YMC15/11/N1073YMC15 / 11 / N1073 ++ YMC16/01/R3958YMC16 / 01 / R3958 ++ YMC15/11/G57YMC15 / 11 / G57 ++ YMC16/02/B372YMC16 / 02 / B372 ++ YMC15/11/B4059YMC15 / 11 / B4059 ++ YMC16/02/N11YMC16 / 02 / N11 ++ YMC15/11/U2284YMC15 / 11 / U2284 ++ YMC16/02/N162YMC16 / 02 / N162 -- YMC15/11/N45YMC15 / 11 / N45 ++ YMC16/02/N394YMC16 / 02 / N394 ++ YMC15/11/N53YMC15 / 11 / N53 ++ YMC16/02/N393YMC16 / 02 / N393 ++ YMC15/11/N54YMC15 / 11 / N54 ++ YMC16/02/N499YMC16 / 02 / N499 -- YMC15/11/N96YMC15 / 11 / N96 ++ YMC16/02/N726YMC16 / 02 / N726 -- YMC15/11/N98YMC15 / 11 / N98 ++ YMC16/03/N942YMC16 / 03 / N942 ++ YMC15/11/N101YMC15 / 11 / N101 ++ YMC16/04/R1602YMC16 / 04 / R1602 ++ YMC15/11/N107YMC15 / 11 / N107 ++ YMC16/05/N235YMC16 / 05 / N235 ++ YMC15/11/N115YMC15 / 11 / N115 ++ YMC16/05/N151YMC16 / 05 / N151 ++ YMC15/11/N137YMC15 / 11 / N137 ++

상기 표 2에서 보는 바와 같이, 본 발명에 따른 박테리오파지 YMC15/09/U2874_KPN_BP는 항생제 내성 클렙시엘라 뉴모니아 53개 균주 중 49개 균주(92%)를 용균 시키는 것을 확인할 수 있었다.As shown in Table 2, bacteriophage YMC15 / 09 / U2874_KPN_BP according to the present invention was confirmed to lysate 49 strains (92%) of 53 antibiotic-resistant Klebsiella pneumoniae strains.

[[ 실시예Example 3] 항생제 내성  3] antibiotic resistance 클렙시엘라Klebsiella 뉴모니아균에Pneumoniae 대한  About 용균성Lytic 박테리오파지의 전자 현미경 분석 Electron Microscopy Analysis of Bacteriophage

상기 실시예 2의 방법에 의해 정제된 박테리오파지를 감수성 균주 배양 배지(20ml LB 배지)에 접종 및 배양한 뒤 220nm 밀리포어 필터로 여과하고, 상청액에 폴리에틸렌글리콜(MW 8,000)을 10%(w/v)의 양으로 첨가한 후 밤새 냉장 보관하였다. 이후 12,000g의 조건으로 20분 동안 원심 분리한 뒤, 에너지 여과 투과 전자현미경(Energy-Filtering Transmission Electron Microscope)을 이용하여 박테리오파지의 형태를 분석하여, 그 결과를 도 1에 나타내었다.The bacteriophage purified by the method of Example 2 was inoculated and cultured in a susceptible strain culture medium (20 ml LB medium), filtered through a 220 nm Millipore filter, and 10% (w / v) polyethylene glycol (MW 8,000) was added to the supernatant. And then refrigerated overnight. After centrifugation for 20 minutes under the condition of 12,000g, the form of the bacteriophage was analyzed by using an Energy-Filtering Transmission Electron Microscope, and the results are shown in FIG. 1.

도 1에서 보는 바와 같이, 본 발명에 따른 상기 YMC15/09/U2874_KPN_BP 박테리오파지를 모양으로 분류하는 기준으로 보았을 때, 파지가 수축성이 없는 긴 꼬리(a long non-contractile tail)를 갖고, 시스(sheath)가 없으므로 시포비리대(Siphoviridae)에 속하는 것으로 분류하였다.As shown in FIG. 1, when viewed as a criterion for classifying the YMC15 / 09 / U2874_KPN_BP bacteriophage into a shape according to the present invention, the phage has a long non-contractile tail and a sheath. Since it is not present, it was classified as belonging to Siphoviridae.

[[ 실시예Example 4]  4] 박페리오파지의Bacperiophage 흡착능Adsorption capacity 및 1단 증식 곡선(One-step growth curve) 분석 And one-step growth curve analysis

항생제 내성을 갖는 클렙시엘라 뉴모니아균을 OD 값이 0.5가 되도록 배양한 뒤, 클렙시엘라 뉴모니아균에 상기 실시예 2에서 정제된 박테리오파지 YMC15/09/U2874_KPN_BP를 MOI 0.001로 넣고 상온에서 배양한 뒤, 100ul 시료를 1, 2, 3, 4, 5분에 1ml씩 채취하여 LB 배지에 희석한 뒤 플라그 분석을 통해 상기 박테리오파지의 흡착능을 평가하여, 그 결과를 도 2에 나타내었다.After incubating the antibiotic resistance Klebsiella pneumoniae to an OD value of 0.5, the bacteriophage YMC15 / 09 / U2874_KPN_BP purified in Example 2 to the Klebsiella pneumoniae bacteria as MOI 0.001 and incubated at room temperature Thereafter, 100ul samples were collected in 1 ml at 1, 2, 3, 4, and 5 minutes, diluted in LB medium, and the adsorption capacity of the bacteriophage was evaluated by plaque analysis. The results are shown in FIG. 2.

또한, 항생제 내성을 갖는 클렙시엘라 뉴모니아균을 OD 값이 0.3이 되도록 배양한 뒤, 4에서 5분 동안 7,000g로 원심 분리하여 세포를 침전시킨 후, 0.5ml의 LB 배지에 희석시키고, 상기 실시예 2에서 정제된 박테리오파지를 MOI 0.001(titer 108pfu/cells)를 넣고 37에서 5분 동안 배양하였다. 배양된 혼합 시료를 13,000g에서 1분 동안 원심 분리하여 얻어진 펠렛을 10ml의 LB 배지에 희석시키고 37에서 배양하였다. 배양 도중 10분 마다 시료를 채취하여 플라그 분석을 통해 상기 박테리오파지의 1단 증식 곡선을 평가하여, 그 결과를 도 3에 나타내었다.In addition, after incubating the antibiotic resistance Klebsiella pneumoniae to an OD value of 0.3, and centrifuged at 7,000g for 4 to 5 minutes to precipitate the cells, diluted in 0.5ml of LB medium, Bacteriophage purified in Example 2 was added MOI 0.001 (titer 10 8 pfu / cells) and incubated for 5 minutes at 37. The pellet obtained by centrifuging the cultured mixed sample for 1 minute at 13,000 g was diluted in 10 ml of LB medium and incubated at 37. Samples were taken every 10 minutes during the cultivation to evaluate the one-step growth curve of the bacteriophage through plaque analysis, and the results are shown in FIG. 3.

도 2에서 보는 바와 같이, 상기 YMC15/09/U2874_KPN_BP 박테리오파지의 접종 후 5분 이내에 박테리오파지의 99% 정도가 클렙시엘라 뉴모니아균에 흡착하였다.As shown in Figure 2, within 5 minutes after the inoculation of the YMC15 / 09 / U2874_KPN_BP bacteriophage, 99% of the bacteriophage adsorbed to Klebsiella pneumoniae.

또한, 도 3에서 보는 바와 같이, 1단 증식 곡선 결과 71 PFU/감염 세포의 높은 버스트 사이즈를 나타내었다.In addition, as shown in FIG. 3, the one-step proliferation curve showed a high burst size of 71 PFU / infected cells.

상기 결과를 통해 본 발명에 따른 상기 YMC15/09/U2874_KPN_BP 박테리오파지는 항생제 내성을 갖는 클렙시엘라 뉴모니아균에 비교적 빠른 시간 내에 흡착할 수 있고, 71 PFU/감염 세포의 높은 버스트 사이즈를 나타내 항생제 내성 균주의 용균 효과를 발휘하는 것을 알 수 있다.Through the above results, the YMC15 / 09 / U2874_KPN_BP bacteriophage according to the present invention can be adsorbed to Klebsiella pneumoniae having antibiotic resistance in a relatively fast time, and exhibited a high burst size of 71 PFU / infected cells. It can be seen that the lytic effect of.

[[ 실시예Example 5] 생체 외 항생제 내성  5] In vitro antibiotic resistance 클렙시엘라Klebsiella 속 균에 대한 박테리오파지의 용균능 검증 Validation of Bacteriophage Activity against Bacteria

항생제 내성 클렙시엘라 뉴모니아균 1 X 109 CFU/ml에 준비된 박테리오파지 YMC15/09/U2874_KPN_BP를 1 X 108 CFU/ml(MOI: 0.1), 1 X 109 PFU/ml(MOI: 1), 1 X 1010 PFU/ml(MOI: 10)의 양으로 각각 처리하고 시간 별로 OD 값(파장 600nm)을 측정하였다. 단, 음성 대조군으로는 PBS+SM 버퍼를 처리하여, 그 값을 도 4에 나타내었다.Bacteriophage YMC15 / 09 / U2874_KPN_BP prepared in antibiotic-resistant Klebsiella pneumoniae 1 X 10 9 CFU / ml was treated with 1 X 10 8 CFU / ml (MOI: 0.1), 1 X 10 9 PFU / ml (MOI: 1), Each was treated with an amount of 1 × 10 10 PFU / ml (MOI: 10) and the OD value (wavelength 600 nm) was measured with time. However, the negative control was treated with PBS + SM buffer, the value is shown in FIG.

도 4에서 보는 바와 같이, 음성 대조군과 비교할 때, 클렙시엘라 뉴모니아균에 대하여 박테리오파지를 처리한 경우 OD 값이 감소하였고, MOI 값이 증가할수록 OD 값은 더욱 감소하였으며, MOI=10에서 가장 억제능이 높았다.As shown in Figure 4, when compared to the negative control, treated with bacteriophage for Klebsiella pneumoniae OD value decreased, and as the MOI value increased OD value was further reduced, the most inhibitory activity at MOI = 10 Was high.

상기 결과를 통해, 본 발명에 따른 박테리오파지는 항생제 내성 클렙시엘라 뉴모니아균에 대하여 용균성을 갖는 것을 알 수 있다.Through the above results, it can be seen that the bacteriophage according to the present invention has lytic properties against antibiotic resistant Klebsiella pneumoniae.

[[ 실시예Example 6] 항생제 내성  6] antibiotic resistance 클렙시엘라Klebsiella 속 균에 대한 박테리오파지의 안정성 평가 Evaluation of Stability of Bacteriophage Against Genus Bacteria

본 발명에 따른 YMC15/09/U2874_KPN_BP 박테리오파지가 온도 및 알칼리에서 파괴되지 않고 안정성을 유지하는지 확인하였다.It was confirmed that the YMC15 / 09 / U2874_KPN_BP bacteriophage according to the present invention remained stable without being destroyed at temperature and alkali.

상기 실시예 2의 방법에 의해 정제된 박테리오 파지 1 ㎕를 4, 5, 6, 7, 8, 9 및 10의 pH로 맞춘 SM 버퍼 40 ㎕에 넣은 뒤, 37℃에서 1시간 동안 배양한 뒤 항생제 내성 클렙시엘라 뉴모니아균과 함께 상기 실시예 4의 방법으로 플라크 분석을 실시하여 그 결과를 도 5에 나타내었다.1 μl of bacteriophage purified by the method of Example 2 was added to 40 μl of SM buffer adjusted to pH 4, 5, 6, 7, 8, 9 and 10, and then incubated at 37 ° C. for 1 hour, followed by antibiotics. Plaque analysis was performed by the method of Example 4 together with resistant Klebsiella pneumoniae and the results are shown in FIG. 5.

또한, 상기 박테리오파지 용액을 각각 40℃, 50℃, 60℃ 및 70℃에서 배양하는 1시간 동안 10분 단위로 각각의 샘플을 클렙시엘라 뉴모니아균과 함께 상기 실시예 4의 방법으로 플라크 분석을 실시하여 그 결과를 도 6에 나타내었다.In addition, the plaque analysis by the method of Example 4 with the Klebsiella pneumoniae in each 10 minutes unit for 1 hour incubating the bacteriophage solution at 40 ℃, 50 ℃, 60 ℃ and 70 ℃ respectively The results are shown in FIG. 6.

도 5에서 보는 바와 같이, 본 발명에 따른 상기 파지는 pH 7에 해당하는 중성에서 가장 안정성을 나타내었고, 14일 동안 산성에 비해서는 알칼리성에서 비교적 안정성을 나타내었다.As shown in FIG. 5, the phage according to the present invention showed the most stable at neutral, corresponding to pH 7, and relatively stable at alkaline compared to acid for 14 days.

또한, 도 6에서 보는 바와 같이, 상기 파지는 64℃에서 20분까지 40% 이상의 활성을 보일 정도로 높은 안정성을 보였다. In addition, as shown in Figure 6, the phage showed a high stability enough to exhibit 40% or more activity up to 20 minutes at 64 ℃.

[[ 실시예Example 7] 항생제 내성  7] antibiotic resistance 클렙시엘라Klebsiella 속 균에 대한 박테리오파지의 전체 게놈 서열 분석 Whole genome sequence analysis of bacteriophage against genus bacteria

본 발명에 따른 상기 YMC15/09/U2874_KPN_BP 박테리오파지의 특성을 규명하기 위하여 전체 유전자 서열 분석을 Illumina sequencer(Roche)를 통하여 통상의 기술자에게 자명한 전체 게놈 서열 분석 방법을 기초로 분석하여, 그 결과를 도 7 및 표 3에 나타내었다.In order to characterize the YMC15 / 09 / U2874_KPN_BP bacteriophage according to the present invention, the entire gene sequence analysis is analyzed based on the whole genome sequence analysis method known to those skilled in the art through Illumina sequencer (Roche), and the result is illustrated. 7 and Table 3.

유전체 번호Dielectric number 범위(Range)Range 개시코돈Initiation codon 스트랜드(strand)Strand 길이(bp)Length (bp) 추정 기능
(Putative function)
Estimation function
(Putative function)
주석 출처
(Annotation source)
Annotation source
(Annotation source)
E-valueE-value NCBI blastP identity (%)NCBI blastP identity (%) NCBI-Bank accession numberNCBI-Bank accession number
시작start 종료End ORF1ORF1 951951 11361136 ATGATG ++ 186186   ORF2ORF2 11391139 15041504 ATGATG ++ 366366     ORF3ORF3 15071507 17821782   == 276276       ORF4ORF4 17791779 19911991 ATGATG ++ 213213 XRE family transcriptional regulatorXRE family transcriptional regulator         ORF5ORF5 21542154 28072807 ATGATG ++ 654654 putative Cro/Cl-type repressorputative Cro / Cl-type repressor         ORF6ORF6 27972797 30483048 ATGATG ++ 252252 serine recombinaseserine recombinase         ORF7ORF7 30573057 31823182 ATGATG ++ 126126         ORF8ORF8 31993199 34053405 ATGATG ++ 207207         ORF9ORF9 34023402 37013701 GTGGTG ++ 300300         ORF10ORF10 37133713 40574057 ATGATG ++ 345345         ORF11ORF11 42054205 47354735   531531         ORF12ORF12 50875087 52005200   114114         ORF13ORF13 52145214 78057805 ATGATG -- 25922592 primaseprimase [Salmonella phage BP12C]Salmonella phage BP12C 00 6262 YP_009300949.1YP_009300949.1 ORF14ORF14 78027802 80838083 ATGATG -- 282282 putative transcriptional regulatorputative transcriptional regulator [Enterobacter phage Enc34]Enterobacter phage Enc 34 1.00E-271.00E-27 4848 YP_007007001.1 YP_007007001.1 ORF15ORF15 84138413 87068706 ATGATG ++ 294294         ORF16ORF16 88188818 91119111 ATGATG ++ 294294 putative Cro/Cl-typerepressor;putative Cro / Cl-type repressor;         ORF17ORF17 91049104 1045310453 ATGATG ++ 13501350 XRE family transcriptional regulator
Cas4-like protein
XRE family transcriptional regulator
Cas4-like protein
[Escherichia phage Utah][Escherichia phage Utah] 00 7474 APD19328.1APD19328.1
ORF18ORF18 1050010500 1113811138 ATGATG ++ 639639 kilA anti-repressor proteinkilA anti-repressor protein         ORF19ORF19 1120511205 1324713247 ATGATG ++ 20432043 DNA polymerase IDNA polymerase I [Salmonella phage FSL SP-124]Salmonella phage FSL SP-124 00 7878 AGF88048.1AGF88048.1 ORF20ORF20 1328613286 1358213582 ATGATG ++ 297297 VRR-NUC domain-containing proteinVRR-NUC domain-containing protein [Salmonella phage SPN19]Salmonella phage SPN19 2.00E-512.00E-51 7979 YP_006990312.1YP_006990312.1 ORF21ORF21 1362913629 1511615116 ATGATG ++ 14881488 DNA helicaseDNA helicase [Escherichia phage Utah][Escherichia phage Utah] 00 7575 APD19332.1APD19332.1 ORF22ORF22 1510015100 1566915669 ATGATG ++ 570570 Endonuclease
TerS
Terminase
small subunit
Endonuclease
TerS
Terminase
small subunit
[Salmonella phage Chi]
[Enterobacter phage Enc34]
Salmonella phage Chi
Enterobacter phage Enc 34
2e-108
2e-108
2e-108
2e-108
79
78
79
78
YP_009101106.1 YP_009101106.1
ORF23ORF23 1565915659 1773417734 ATGATG ++ 20762076 RecT family
Recombinase
Terminase
large subunit
TerL
RecT family
Recombinase
Terminase
large subunit
TerL
[Salmonella phage FSLSP030]
[Salmonella phage Chi]
Salmonella phage FSLSP030
Salmonella phage Chi
0
0
0
0
80
79
80
79
YP_008239842.1
YP_009101107.1
YP_008239842.1
YP_009101107.1
ORF24ORF24 1773717737 1799717997 ATGATG ++ 261261 head-tail joining protein lambda Whead-tail joining protein lambda W [Salmonella phage FSL SP-019]Salmonella phage FSL SP-019 8.00E-348.00E-34 8080 AGF89268.1AGF89268.1 ORF25ORF25 1799717997 1966119661 ATGATG ++ 16651665 putative lambda family portal protein putative lambda family portal protein [Salmonella phage iEPS5]Salmonella phage iEPS5 00 7777 YP_008240291.1YP_008240291.1 ORF26ORF26 1965819658 2099820998 ATGATG ++ 13411341 prohead protease ClpP
capsid maturation protease
prohead protease ClpP
capsid maturation protease
[Salmonella phage FSL SP-019] [Escherichia phage Utah]Salmonella phage FSL SP-019 [Escherichia phage Utah] 5E-173
4e-170
5E-173
4e-170
65
63
65
63
AGF89266.1
APD19337.1
AGF89266.1
APD19337.1
ORF27ORF27 2101121011 2140021400 ATGATG ++ 390390 decorator proteindecorator protein [Salmonella phage FSLSP030]Salmonella phage FSLSP030 1.00E-581.00E-58 7676 YP_008239846.1YP_008239846.1 ORF28ORF28 2141321413 2247722477 ATGATG ++ 10651065 capsid proteincapsid protein [Salmonella phage FSLSP030]Salmonella phage FSLSP030 00 8787 YP_008239847.1YP_008239847.1 ORF29ORF29 2252822528 2279722797 ATGATG ++ 270270 general stress proteingeneral stress protein         ORF30ORF30 2279922799 2316423164 ATGATG ++ 366366         ORF31ORF31 2316423164 2378423784 ATGATG ++ 621621       ORF32ORF32 2378123781 2428424284 ATGATG ++ 504504         ORF33ORF33 2429824298 2543725437 ATGATG ++ 11401140 major tail proteinmajor tail protein [Escherichia phage Utah][Escherichia phage Utah] 3.00E-1683.00E-168 6565 APD19344.1APD19344.1 ORF34ORF34 2554425544 2600226002 ATGATG ++ 459459 XRE family transcriptional regulator
tail assembly chaperone
XRE family transcriptional regulator
tail assembly chaperone
[Salmonella phage Chi]Salmonella phage Chi 4e-534e-53 5757 YP_009101119.1YP_009101119.1
ORF35ORF35 2604426044 2624126241 ATGATG ++ 198198 XRE family transcriptional regulator
pre-tape measure frameshift protein
tail assembly chaperone
XRE family transcriptional regulator
pre-tape measure frameshift protein
tail assembly chaperone
[Enterobacter phage Enc34]
[Escherichia phage Utah]
Enterobacter phage Enc 34
[Escherichia phage Utah]
7E-25
9e-16
7E-25
9e-16
71
69
71
69
YP_007007021.1
APD19345.1
YP_007007021.1
APD19345.1
ORF36ORF36 2623426234 3054730547 ATGATG ++ 43144314 tape measure proteintape measure protein [Salmonella phage BP12C]Salmonella phage BP12C 00 6666 YP_009300926.1 YP_009300926.1 ORF37ORF37 3055130551 3333733337 ATGATG ++ 27872787 conserved tail assembly proteinconserved tail assembly protein         ORF38ORF38 3334133341 3418934189 GTGGTG ++ 849849 XRE family transcriptional regulatorXRE family transcriptional regulator         ORF39ORF39 3419834198 3442534425 ATGATG ++ 228228 siderophore-interacting proteinsiderophore-interacting protein         ORF40ORF40 3442234422 3462834628 ATGATG ++ 207207 tail assembly proteintail assembly protein         ORF41ORF41 3462834628 3691336913 ATGATG ++ 22862286         ORF42ORF42 3691636916 3769837698 ATGATG ++ 783783         ORF43ORF43 3774537745 4035440354 ATGATG ++ 26102610         ORF44ORF44 4035940359 4145341453 ATGATG ++ 10951095         ORF45ORF45 4151541515 4167341673 ATGATG ++ 159159         ORF46ORF46 4180741807 4212942129 ATGATG ++ 323323         ORF47ORF47 4208642086 4222942229 ATGATG ++ 144144         ORF48ORF48 4222942229 4256142561 ATGATG ++ 333333 siderophore-interacting proteinsiderophore-interacting protein         ORF49ORF49 4257442574 4315843158 ATGATG ++ 585585 endolysinendolysin [Pseudomonas phage JG004] [Pseudomonas phage JG004] 2.00E-522.00E-52 4747 YP_007002453.1 YP_007002453.1 ORF50ORF50 4315843158 4354743547 ATGATG ++ 390390         ORF51ORF51 4354443544 4380743807 ATGATG ++ 264264         ORF52ORF52 4383143831 4403144031 ATGATG -- 201201         ORF53ORF53 4402544025 4479844798 ATGATG -- 774774         ORF54ORF54 4479544795 445091445091 ATGATG -- 297297         ORF5ORF5 4509145091 4538745387 ATGATG -- 297297         ORF56ORF56 4538945389 4559845598 ATGATG -- 210210         ORF57ORF57 4560145601 4594845948 ATGATG -- 348348         ORF58ORF58 4595245952 4646446464 ATGATG -- 513513         ORF59ORF59 4654046540 4725347253 ATGATG -- 714714         ORF60ORF60 4725047250 4757047570 ATGATG -- 321321         ORF61ORF61 4757247572 4832148321 ATGATG -- 750750 putative head morphogenesis proteinputative head morphogenesis protein         ORF62ORF62 4832148321 4955949559 ATGATG -- 12391239 siderophore-interacting proteinsiderophore-interacting protein         ORF63ORF63 4962049620 5068150681 ATGATG -- 10621062 putative C-specific methylaseputative C-specific methylase [Escherichia phage K1-ind(3)]Escherichia phage K1-ind (3) 1.00E-1071.00E-107 5555 ADA82477.1ADA82477.1 ORF64ORF64 5081950819 5119651196 GTGGTG -- 378378         ORF65ORF65 5118951189 5145251452 ATGATG -- 264264       ORF66ORF66 5145651456 5167151671 ATGATG -- 216216         ORF67ORF67 5167451674 5238452384 GTGGTG -- 711711 putative DNA adenine methylaseputative DNA adenine methylase [Salmonella phage FSLSP030]Salmonella phage FSLSP030 6.00E-1046.00E-104 6363 YP_008239882.1YP_008239882.1 ORF68ORF68 5237752377 5269752697 ATGATG -- 321321         ORF69ORF69 5269452694 5301453014 ATGATG -- 321321         ORF70ORF70 5301153011 5349353493 ATGATG -- 483483         ORF71ORF71 5348353483 5389053890 ATGATG -- 408408         ORF72ORF72 5388753887 5465454654 ATGATG -- 768768         ORF73ORF73 5481154811 5508355083 ATGATG -- 273273         ORF74ORF74 5508555085 5531255312 ATGATG -- 228228 major capsid proteinmajor capsid protein         ORF75ORF75 5531455314 5638456384 ATGATG -- 10711071 exonuclease RdgCexonuclease RdgC [Salmonella phage FSL SP-124]Salmonella phage FSL SP-124 2.00E-1622.00E-162 6565 AGF87999.1AGF87999.1 ORF76ORF76 5637456374 5670656706 ATGATG -- 333333         ORF77ORF77 5670356703 5701757017 ATGATG -- 315315         ORF78ORF78 5701457014 5724757247 ATGATG -- 234234         ORF79ORF79 5724057240 5768657686 ATGATG -- 447447         ORF80ORF80 5769957699 5804358043 ATGATG -- 345345         ORF81ORF81 5802158021 5844658446 ATGATG -- 426426         ORF82ORF82 5854258542 5891958919 ATGATG -- 378378 replication protein DnaD
RecT family protein
replication protein DnaD
RecT family protein
[Salmonella phage 37]Salmonella phage 37 1e-281e-28 5050 YP_009221455.1YP_009221455.1

도 7 및 상기 표 3에서 보는 바와 같이, 상기 박테리오파지의 전체 유전자는 59087bp/ GC:56.33%의 linear dsDNA로, 82개의 ORF로 구성되어 있었으나, 그 중 36개의 유전자 만이 기능적 단백질을 코딩하였으며, 대부분 가설 단백질(hypothetical protein)로 분석되었다. As shown in FIG. 7 and Table 3, the total gene of the bacteriophage was 59087 bp / GC: 56.33% of linear dsDNA, which was composed of 82 ORFs, of which only 36 genes coded functional proteins. It was analyzed as a hypothetical protein.

또한, 본 발명에 따른 YMC15/09/U2874_KPN_BP 박테리오파지가 용균 효과를 나타내는 단백질을 코딩하는 유전자의 서열은 ORF49(endolysin) 등에 해당하였다.In addition, the sequence of the gene encoding the protein YMC15 / 09 / U2874_KPN_BP bacteriophage showing a lytic effect was equivalent to ORF49 (endolysin) and the like.

본 발명에 따른 YMC15/09/U2874_KPN_BP 박테리오파지의 서열을 기존의 박테리오파지의 서열과 대조한 결과, 본 발명에 따른 박테리오파지와 유사성을 갖는 박테리오파지는 검출되지 않았다.As a result of comparing the sequence of the YMC15 / 09 / U2874_KPN_BP bacteriophage according to the present invention with the sequence of the existing bacteriophage, no bacteriophage having similarity to the bacteriophage according to the present invention was not detected.

상기 결과를 통해 본 발명에 따른 YMC15/09/U2874_KPN_BP 박테리오파지는 기존에 발견되지 않은 신규한 박테리오파지에 해당함을 알 수 있다.Through the above results, it can be seen that YMC15 / 09 / U2874_KPN_BP bacteriophage according to the present invention corresponds to a novel bacteriophage not previously discovered.

이상에서 본 발명에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고, 청구범위에 기재된 본 발명의 기술적 사상을 벗어나지 않는 범위 내에서 다양한 수정 및 변형이 가능하다는 것은 당 기술분야의 통상의 지식을 가진 자에게는 자명할 것이다.Although the present invention has been described in detail above, the scope of the present invention is not limited thereto, and various modifications and changes can be made without departing from the technical spirit of the present invention described in the claims. It will be self-evident to those who have knowledge of.

한국생명공학연구원Korea Research Institute of Bioscience and Biotechnology KCTC18571PKCTC18571P 2017051120170511

<110> Industry-Academic Cooperation Foundation, Yonsei University <120> LYTIC BACTERIOPHAGE SPECIFIC FOR KLEBSIELLA GENUS RESISTANT TO ANTIBIOTICS <130> DPB172743 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 59087 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15/09/U2874_KPN_BP <400> 1 atggccaccg tggcgccgca ggaattttac ctcaaggatt gccgggcatg gccaccggtc 60 aggcccatgg cgccgacctg gctggcgcgg cccgccgccg ggtttcagcc tgccagcttt 120 ttcaagtaag cgcgcaccgc taaaaatttt cagcccgcta ggtttgccaa gtaaggaagc 180 ccaaaatttt tatagaaaat ccggatttcg gcgtccccat ggatcccgaa aaaggtgcga 240 tttctgtaaa ccattgattt tattggttcc gcggggatgg cgccgatggg gcggaaaggc 300 cagcaagcca ggcgtggcgc gggttgcatg ggtatagatc cccgttgggt gacggcgtgg 360 cggcgcgccc tggggtgacg cggaaagcaa aaatgaaata aatctgcatc gaggggttgc 420 acacggaatg agtgcaagtt atgtttatcg aacccggcgg ggatacgcga acaacgaaac 480 aacataaacg aggtaaacga aatgaaaaag attaaacgtc tggcactgtc ctggtctgtc 540 tcccgcggtc gtgacactta cggctacaac atttgccgcc ttgatgacac atcaaccgga 600 gaccgcttta aatgcatggg cggcgggtat gacatggtag ggacggtgtt cggtgactgg 660 ctggccgcaa actatcagcc tgaattgttg gcgctgaaag atcgcgctgg ggccgtgtgg 720 gaagaggcgg gcggccgtaa atcggcggac cgcgcggacc gcctatacgg catggtatac 780 cgggaaaaag atagcgtagt tatccttgat ggcgcttgcg ggcttgattg catgatccgc 840 attgctgagg ctatcgggct ggaagtggag cgcgattata tcgctaaagg ccgccgccgg 900 ggtgagactg tgggctggta tgtaagcgag gccgaataat gataacaata atgtttatcg 960 gttatttcat tatcggcgtt tatatcgggg cggacgtccg ccgcgtttta aagcgttgcc 1020 gtattgagcg ccgcccgtgt tttggtcgca tgactattta tttgcgtgaa cgtaagaccg 1080 gacggttgat cggctgttct aataacattt tcactttaat tttgcagggg tcttgatcat 1140 gagaattaaa atagaatcgc ataaatatgc gccggaatta aaccgcgttt atttaaccgg 1200 aaaaaattca tcgagcgcgg cggtactccg cgccccgtcg gtaacgtccg taaaagatgc 1260 ccgcgcggcg ttattcccta aagcgcttcc attccgccgg gttgtaaccg tggaatcata 1320 ttatgatgat cctcgttttt acgggcttgg ccgccgctat tccggaaccg tggattcata 1380 cgaacatctt aaaaacgtga tcgctaacat taaagcccgt aacactgggg ggccgctgtt 1440 agatgggtcg attctcccgc cagtgaaagt gcgtattgtc tcaataaaag ctatgggggc 1500 ttaattatgt ttacctcaaa cgttgaaaac cgtctggcat tgccagccgt cattaccgcg 1560 cccggcgact acatcacccg gtccggatgc cgcgtcacaa tcatcggggt atcgcctgtt 1620 aatagccatt ataccttccc ttgcaagggg tcagtatggg ttaaattccg cggggcgatg 1680 cggccgcgtg gatataacgt ctggatgcgg tccggtcatt tacacgccgt gggcgatcat 1740 ccgctggata tcgtcgggcc gtgggaggac ttgaaaccat gaatagtgac gcaaaaaagg 1800 ccgtcgtaaa gttctccgcg tgcggcctta tcgctggctt taccgtgatc gccattatcg 1860 cgggcgacgg gggcggcctg ttccgcccga tactttacac cgtggctgga ggggtatgct 1920 gtgggctgat atggcccaca caggaccagg gcgacgccct gctggactgg atcaaagaag 1980 ggcggcgata agccgccttt cttattggcg ctgatacccg aaccgcgaaa accggggtga 2040 cgcggacagc aaaaatgaaa taaatccggc taaggggttg cactcgttcc gtgtgcatat 2100 tatgtttatc ggacccggcg gggatacgca aacaacaata aacgaggttc aaaatgacat 2160 acgacgaaat caccgcaaaa attaacgctt tcaacctgaa agatgggatc acgattcgtt 2220 atacctccga cacggacgga tcaaccctgg ttgaactccg cgacgatagc ggcgctttga 2280 tctggtgtgc ctggtccttt gaggctgatt ttgctttctg cctggatcgc gagctggacc 2340 gctacggcgt gaacaaatca gcggaggcgt attgcgtcgc tgataaccgc cgcccgtccc 2400 acgtaaaccg cgcggactac gcaacggacg ccgaatacag cgccgcgaag gtggcgtttt 2460 atgcgcatat actccgatcc ctgtggtccg tacgcgggaa cagcatttac cgtcgccagg 2520 taaagaaaac cattaaatca ctgcgagact ggaaagcggt cgcacgcaag gacgcggacg 2580 ccgccggggt ggcggcggta ttcggtaacg ccctcatggt taaacccgtc aaaatcacta 2640 cggcgggcgg aatgaccctt atcgcctcgc aatccgatat aaagatctac ccggctttaa 2700 tgcgcctaac ggcattgtgg gatatgcgcc acggcctaac ccgtgacacg cattacaacc 2760 attctctgcc gttccactgc atcgcgggga ttgaatatgc gggctaacga tattcgccgg 2820 gcgcaagccc gttacaccat ggaaaaatgg cacgggaatt tagtcgccaa aggctttaaa 2880 gcggctggcg atctgctgta tagccgaaat gatgccgatc taacgtggga tgacaaggcc 2940 cgcgcctgga cggtgactat ctggaccacc gaggggcggg accgtctcaa agtgctaact 3000 attcgcaaaa atccggtttt accggcgtta cttaaatctt ttttctaggg gtatctatgt 3060 tcgcattccg tgatgttctg gaagtcgttt taccggcggt aatgttcgcc gtggcgcttg 3120 tcgtcatttc cagtgattac cgtcgtaaac tccgcgccag cggtcgtaaa ttcaaaaagt 3180 aagaaggggg gaattattat ggcttcggta tggtttttag tggtgacact gtgcaccgtt 3240 aaccctggcg cgctggcgtc ggattgtgat gactatgtga tcgacgggga tttgtcgtat 3300 agcgattgca tcaagtccat cgcacagttc ccggagaagg ctgcattgtt cgcggtcagc 3360 tgtaagcgcg gggaaccgct ggacggcgta gggggtgaga tgtgagtaac tttaaaacgg 3420 atgtaaaagg gtcagtagtc ctactgtaca aggacgataa cctacaaaag ccggtcgcta 3480 ctgtgaacag cgcggatgac gtggaggata tgcgcgggca aatcagagac gcggttatgg 3540 cggcctatca tatcggcgtt atggagggtt tcaatgaggc taaaagtgaa ccgctgaggg 3600 atgacccgag agttatcaag gcgctacaac gcgccacaaa agccgggcgg gaacagcacg 3660 ccgcgcaact ccgcgcgcta ctgaatgaag gtcttaacta gggggaagaa aaatgaaaaa 3720 acgtctgacc gttctgattt gtaatgatat gcgcgacccg tacgatccga ttgtggtaac 3780 ggtgagcggg gcgacgcctg aagaagtccg cgccagtgcg ataatcgcgc atgctgaggc 3840 ggaaatggcc gactttgacg gcgaccctat gacggcggcg gatctgtggg cggtatcgcg 3900 ggcttacatc ttcgcggcta tccccgggac cgtggatttt tactatgtcg ggatgccatc 3960 ggacacggtc gacaattacg atcacgtgat gggtgagatc ctgcatgtga tgggtgagag 4020 cctggacacg tcgcccctat gcaacatggg cgattaaccg cccgccgtat tcccgcccca 4080 taaggcccgc catttgagcg ggtcttttta cgtctgcctt atacccgaac ctacgtatcg 4140 cagcctatcg ccctggccgc tggcatagcc cccggagtga ccagtggatg aaaagaagtt 4200 gcactcaccc cgtttcataa aatacccctt tacgccgtcc taacagcctt tttgaaatca 4260 gattaattgc acgcggtgca ggtgcatccc tgcccggtgg cgggcgcgtt atatcgtgct 4320 gtgggctttc tgtattgcac acggggcgtg tgttataggc gctgcccttg tgtgaccgta 4380 tcaatgcacc tgatgcatgt tcaatgaggc cgcttatcgt agtgatatgg cctgtttttg 4440 tgtcggggtg gtggtgtgac cgtgtgacct ggtgacggta tgccaattct gccgccgcta 4500 cggggggtag acggggcgat cgtgggggta tgtagtaggg gtataccatg atcggggttg 4560 cggctgtctc cgtggcgctg gcgaaggaat ccggatcgaa ttcaaaaagg tacttcccgg 4620 gggtcctggc gtgccggggg tgcgcagagc cgcggtggaa gaaaatgcgg cgaaaccccc 4680 atagccccac ttcggaaatt cctgatttac aggggttttt tcgagttttg cccataggga 4740 agacgtgatt ttgcgttcca ggggtggtgc cctaaattcc gttttagccc cgcaaccgat 4800 tgattgcatt acatttttgg gcggtgctct tacaggatca ggtgtcgtca cggaaggtgg 4860 tttattacaa attacaagtt tactacaaga cgaacaactt gtaataaacc ggtaagctgc 4920 tgttatttat atcttttcct caatatttat tacaagttac aagaaaacaa ggaaatccat 4980 ataagattaa aagtaaaacg taatcggtat gcatattatg tatatgtata agtaacctca 5040 acttgtaata aataataatc gcgaaaaatg atttgcattc aaacacttgc aaattattac 5100 aagtttgccg ccccccgaaa actggtcaaa aacggccatt tttggggaca aaaaacgcga 5160 tttttcgaca aaaaagaaag gggccgaagc ccctttttag cgatttttct tgctcacact 5220 tcgtcatcgt cttcatcgtc gaacggattt ttcggtttcc cgattttctt ttcgacttcg 5280 gcattgtgtt ttttgagcgt agtttgcgcc cattttgtat tcagcgtacc gttttcctgg 5340 aacgcattac gcacacgttt tctgacgaac actcttccgc ttttactatt gaaacagagt 5400 accccagctt gagtaaaacc gagttccatg agcaggtttt tcatgcgtga agtcttcggc 5460 atctcgatgc cctcggcttc cataaatgcg tcgttcaatg atggtgaaaa gataatgtct 5520 ttgcacacgc ccagtgtcac gccgcccttg atcatgtccg ctataaattc gcctgcgccg 5580 tcgttcgctg catcgcgcat ttcgcggaaa gcattagtat ccaacggggc atggccttta 5640 tggttaaacc cctccgagat ctcccattcc atgaaccact ttttgatggc cgcgctgtga 5700 ttttcgatag cccgataaac gttagagaag aacttctcgc gttccttagc cgagccgtaa 5760 acgcggtcca tgtccatgtg gttttcagcc tgcgtggaga cgaccaggta gcggcgctgg 5820 ttctcatcca gcggaagcgc gttgatgtgg ttggtgaaca tcaatttcga actggtattc 5880 accacgtcac gcggctttac gcctttccct tcaacctgga agcggtcgtt cgagataaat 5940 tccttctgtt tgtcgaccgc gctgtaccga tcacccttgt catacacctc ttccacgatt 6000 ttcagaatgt ggccttccgc ccagtcggtg aaacgaccat tcatgaccga gtttgacacg 6060 tacccgatgt tctgggcgcc gagcatttcc cgcatgagca cgccgatggt cgatttaccc 6120 gaaccgtgag caccgcggat cagaagagag tagttaattc gctttgtcgg gtgctgaacg 6180 acgtgcgcca gccagtccat gacgtaattt cgctctttcg tgtccggaaa caatacgacg 6240 aacaggtctt tgacgatcga gatggccttt ttatccagtt ttgacagctt ttccgctggt 6300 ttagggatac tttcaggcga aaaagtgttt aaacgtagca aaccggcgtc gtcatagaag 6360 aattccggcc ctaaaagtcc ctctttttgg gtccatttcg attcaggcat atccccgtgc 6420 atttcggggt agtacataac atcgtgaata atagggattt ttacgacgtc cgtggcgaac 6480 ttattcggcg ataaaccgcc ttccacgtcg ccgatatcac gcccatggga cgaatcaaac 6540 gcgctttttg acagtaaaat cccggtttta cggctaacaa aggcgtcctg ggcctgggca 6600 aagacgtatt ctttcagcca agtcggggta tccgcacggg aaaagtcgaa actgaggtac 6660 tctttaacgg ctttgttagt cagcgcgctt tcgttcaggc gtttgtaggc tttcttggcc 6720 gcgtcaatag tcggctggcg ctcaatgccg aaaacccgca gcttacggaa gtcgtctgcc 6780 caggctttcc agtccgccat ggtggtgact tcgttgaatg cctcggtgaa ctcggaaacc 6840 tgttcccggg cttccttctc ttcgatttcg tggaccgttt tgatgatggt gccgattgtc 6900 accagcgtct gggcatcatg ggtaaagcct ttttcccact tgtactcgaa ttctgactcg 6960 tcatagttat ccgcctgcat ggaccagtcg cgggcgatct ctttcgcttc atcctgatcg 7020 cggcatgaca cctgcagcgc tgccattacc cggatccagt tttcatagtt ttccgggtca 7080 gggtatttca tgacgatatc gcgcagctcg tcgtaggtgc cgtcccactt ggtgacggtg 7140 gccattgccg cccagtcgtc atcgtccgct tcgccttccg ccgcccgccc gttaatggcc 7200 cgtgcgactt tcatccatcc ctgtttttcg gcataggcgt cgaacgcgtc ggcgatatcg 7260 cgggcgatct ccagcgttat ttccggcagg tccatggcgg ccgcgcagtt caccggggta 7320 tcatcggtga tccaggtgta ttccttgcgc gtatccgggt ggataccgaa ggcgacgaac 7380 tgctggccat cacccaggat ttcgactgca tggcgctgtc cgaagtcatc ttcccaggtg 7440 gcggacttga cctttttgaa cggctcgtcg gtatggcaaa gcaccagttt tttcggttga 7500 cggccaacac gaaccgggcc ggcgccgatt ttcttttcga caacggccat catgtgctta 7560 accccgtctt tgtcgtagac gtcaatgtct accgcggggg tgtgcttggt caggatgccg 7620 atgccagatg acgcgtattt cttcacgaaa ccgttaatct ggccacgggt attctcgatt 7680 ttctgccagt cttcgaacgc aggccgtttt cctgcttttg gcctgggcga gtcaggcgga 7740 atgatgggaa cgacggtgaa gccgttttcc cacagcacta ttccgtattc gttccagtag 7800 ttcattcaag aatttcccct gtatccgggt cgatttttat ccagtccggg ttagtgaacc 7860 aatgtggtcg gatgccagaa gttttagctg cctcacaaat tttgacggcc atctgtccgg 7920 aaacggtgtt gcggatattc cagatcatag tgtcgtaatt tacgccagcc gccttcgcca 7980 gtttggtaag gttgccgtcc gggtctacct ccagggcagc gatacccgcg agataacgcg 8040 gtctcaggga gtggtcttta atagcccacg gtggaaattt catagatgat cctcgcgtgt 8100 gtgtgcgtgt aagtaaaacg gatattagtc tcgcgctgct acaaagtaaa ggggacgata 8160 cccggcgacc cccggccatt tcacaaagat ccccgaaaaa accaatgggt accgaaaaat 8220 atttttgcga aagtgttgac acgggatgcg gcaatggcca tactccaaac cgtcaacacg 8280 acaaacccaa attaaccgaa cgaggattta actatgtcag gtatttttga acagctgctg 8340 gccgaacaac aaaaaaccaa ctccctgctg gaacagctgc tggcgaatgg cggtgtttca 8400 tccgctgcag caggtgaaga cgctggcgcc ggtaagacca ccgccaaagg taaaaccacc 8460 gccaaaggca aatccactgc tgcggcagac aagccgaaac acaccaaaga cgaagtagtc 8520 gctgcggtcg tagcggtgaa agaccgcttt ggcgcaccgg aagccaaaaa gatcaccgct 8580 aaattcggcc tggccaaaat cgccgaagcg aaagaagaac acttcgacgc gatctttgac 8640 ctgtgtgaag ccaaactggc cgaaccggaa gaggatgaag gcaactccga agaagacgac 8700 gtttaatctt cgatcgtgta actcggcccc tgcgggggcc gttttagcag agaggttatt 8760 gtgaataagt tcggaacggc aatagcgatg acgcccggcg gcggagagga agtgcctatg 8820 tgggctgagt tccgcttcga aattggcgac cgtaacccct tattcagagt aacttccccc 8880 gcgcgtggcc agaacggccg gcggattaac ggggaattcc gtttcgtcgt tacccacgtt 8940 gggtccgggt atcgttttac cgatttcagt ttcgacctgt tagcgaaaac ccggtataac 9000 ctgaaacgga ataactacgg aagggccggc gcaatggcgg ttaaaaagac aatcgatgaa 9060 gtaggcgttg aacgaatttt acgcgccata aaaggctacc atgatgagta agtctttcct 9120 ggttcgtgtt atgcaggagt ttgccggcgg cgggcattct atcttcgcgc cgtcagcctc 9180 tgcgatgtgg acggcctgcg gcggaagcct gctggccaac cttttcgaag aggacgagtg 9240 cagctatgaa gcggcggaag gaaccgtcgc ccatggcatc gccgagcagt ggctgaaaac 9300 ggacatccga ccgacgcatc ttatcggaac cacgcaggtc atcgaggaaa aaggcgttcg 9360 gcatgagatt gtcgtcaccc actccatgat cgactacgtt caggattatg ttgactggtg 9420 tcggttcgaa gaaggcatga tgctgacgga aatccgggtc tggttcaccg acctgatgcc 9480 gccagccaac gctgacgagc tggaggaaga cccggacgcc gaagtagtgc cgtttctccc 9540 gcagggcggt accgcggata acatcatcat tcgtgaccgg gtgctgattg tcaccgacct 9600 gaaatacggc accggcgtcc aggttttcgc ggaaggcaac ccccaggcgt tgctctatgc 9660 atacggggcg taccgcgcat tcagcgacga gtacgagttt gaccgggtca tcatccggat 9720 cgcacagccg aggcttgagc atttcgacgt ttgggaagtg acagtcgacg aattgctgga 9780 cttcgccgag tttatccgcg agcgtgcagc ggccgcctgg tcactcaaag ccaaacgcaa 9840 ggcgacgttg aaaggatgcc gatggtgccg ggccgcgcat aattgcgcag cggtggcgta 9900 catgatggaa tgcgccgtcg gtgccgacct cgaattcctg gacactgaat tcggagatta 9960 tgagatgtcg cagttacgct ccgccctggc ggaagaatac aaaatgcgga aggcaaagtt 10020 cggcgatctg tccgttgccg agatggccaa gatcctgccg taccgcaaag tgattgaaaa 10080 ctggttcgcc cgcctggacc tggaacttga gcgggccgcg aaagacggta aggcggttcc 10140 cgggcataag ctggtggaat cacgctctaa ccgtgcgcat accaacgtcg aaaaggccaa 10200 ggagctttat gatttcctcg gccttgacga aaaagactat atgaaaacgg aattgcgctc 10260 gccggcgcag atggaagaag tccttcggga taaacttgga ctgtcacgcg ccggcgcgcc 10320 aatggtcatc gaaagcgtcg tatggaagcc ggaaggcaag ccgaccctgg taccgctcac 10380 tgataagcgg ccaccactgg atcggaaata ttccggcgcc tatgatgacg aagatgacga 10440 tgatgaagtg taaatcggta agatggtaaa cccgtaaatt cgtaacccgg agtagagaaa 10500 tggctgaaaa attaattccc gcgaagaaag ttaaaaacgg cgttctgtat aagagcggtc 10560 acatcaaagt ttccaacgta cgcgcttcat atccgcacct gggcgcccca tacggcggag 10620 acggcgaagg cgagccgaaa tacggtatcg ttgggctttt gccgaagaaa acgcacaaag 10680 agatttacca gctgctgaaa gagcagatcg aagtcgccaa aaagaatcac aaagctggtc 10740 cgctcaaagt ggcgccggcc atgttgttcc tgaaagacgg cgatgtcgat ttcccggaca 10800 aaccggaatg cgctggcatg tgggttctct ctgcgcgcga aagcaaaaag cccgaagtct 10860 ttaacatcga gcgcgaggaa ttaacgacta aggctgagat tgaagaagag atttacggcg 10920 gttgctgggt atccatggtt atccgaccct ggacccagga taacaaatac ggcaaacgcg 10980 taaacgctaa cctgatctct gttttaaagc gtaaagatga cgaaccgttc ggcgaaggtc 11040 gtgttgatac ctccgacgcg tgggatgacg acgaagactg ggaagacgac gaagactggg 11100 aagacgacga cgccggcgac gaagacgacg acgtttaacc cccagcccgt cgggcattga 11160 aaccggaagc ccgcctagtg cgggctttct tataagagga caccatggcc gatattatta 11220 accttgacta cgaaagccgg gcgcgtgcca atctcaaaac gcaaggcctg gaccaatatt 11280 cccgctgccc ggatgcgaaa gtgctgatgg cggcgtattc ccttaacaac ggtaaggtgc 11340 agcacgccga cctatcccgt ggcgcgaaga tgccggcgga gctgaaagaa gcactgcttg 11400 acccctacgt ggagaaatgg gcattcaacg cacaattcga aagggtgatg acccgccgtg 11460 ttcttggtct gaaaaccccg tacaaatcgt ggcgatgcac gatggttctg gcgtacatgc 11520 tcggcttcac tggcgacctt ctgcagatag gtaagcaggt cgggctgaaa gaagaccagc 11580 tgaaagacac ggacggcaag cggctgataa aaatgttctg cgtgcctcaa cgtgtcacca 11640 aaaataaccc ttttgaatgg cgtaacgagc taacggatcc cgaagagtgg tgggggttct 11700 gccggtataa cattcgcgac gttgatactg aaatgctgat caaaaatcgg cttatcaagt 11760 accccatact gccgcaggaa tgggacttat acgccctgga ccagcttatc aatgaccgcg 11820 gcgtaatgat cgacaccgaa ttcgcgcagg ccgcactgga cctggctgaa cgccggaagc 11880 cgcaaatcat agaagagatg aaggatatca ccggccttca aaaccctaac tctgtatccc 11940 agctagtgcc atggcttaaa gagcgagggt acccgtttga cgatgtgcgc caggacacgg 12000 tgaaaaaagt tatccgtgaa caggaagaaa acggcgtcga tgatgaagcg ataaccgttc 12060 tgaaagcccg ccttaacagc gccaaaaact caatcgccaa atataaaacc atgatcgact 12120 gcgccgggga ggacgggcgt ttccgttact ccctgcagtt cgccggcgcc agccgaacaa 12180 atcgctgggc cggacgccgc ctgcagacgc agaacctcgc gcgcaccccg aaatttcttg 12240 agaaagtgga agacctgacg atcgcgaacc ggttcatcgc gaaccgggaa ctggataacc 12300 tggcgctgtt cgccggggaa ccgatggacg cgcttgtcgg ctgcatccgg tcagcaatca 12360 tccccgcgcc gcagcataaa tttatcgtcg ccgacctttc atccatcgaa tcggtagtta 12420 tcggatggtt gaccgactgc aaatggttca tggatacact ggcggcaaag catgacctgt 12480 atcagtcatt tgctgcccac tggctcggaa taccgtacga agacaccctt cctcaccgca 12540 gtaaagccaa acccgctacc ctcggtgcag gttatcgcct tggtggcggc cacctcggcg 12600 atgacgggaa gaaaaccggg ctgtggggat acgcggagaa tatgggcgtt cacatgaccc 12660 agaaagaagc cgcggattcg gtgaaagcgt tccgcgaact ttgcccggaa atagtgaacg 12720 cctggacgca gctggaaaac tgtgtcttcc aggttatccg tacgcaccgt ccggttaagt 12780 ggaaatgcct gaccatcgaa tacaccaagc cattcctgac tattcagctg ccgtcaggcc 12840 gtaagatgta ctacttccgc ccgcgcatcg ctgaacgcca gatgacggtt cagagcggcc 12900 cacgtaaagg cgagaagtac agcacactga acttccagta cgaagggaag attgaaaaat 12960 ccggcggttc gtcctggggc aaagtgttca gccacggggg gaaacttgtg gaaaacatcg 13020 ttcaggccct ggcgcgtgac gtcctcgccg aagggatgaa gaaggcacac cggatgggat 13080 ttaagatcgt catgcacatc cacgatgaga tcgtcaccga agtcccggaa gatagtccgt 13140 taacccttgc tgacctgatc ggctgcatgg cggctgaact gccatgggcg cccggattgc 13200 cgcttggcgc cgccggatgg gaagggtatt tttatcgcaa ggactaattt gcatagaaat 13260 caaagacttg ccggagaaac cgctaatgcc cgaatgggga acccctgtcg tcagggaatc 13320 gaaggtcgaa ggccgctgct gcgagtatgc gcagggccgc ggctggtggg tgtcgaagtt 13380 cacggcacct gggaaaaagg ccgttccgga ccgcgttttt atccggaacg gcgttgtgct 13440 ttttgtggaa ttcaagcgcc cgggcgaaga accaacgctg cagcagcgaa accgccatcg 13500 gcagatgaaa gccaaagggg ctaacgtgac atgggtggac aattttgaag actttaagaa 13560 ctaccttatc tcctttgagt aaggcaatcg cgtattgcca gcgcaacgtg attcaccagc 13620 ggtcggacat gcacggctat caggacgagg gcgtcgactt catcaaagaa acgccgttct 13680 gtggcctgtt cgtcgacctc ggcctgggca agaccgtgat ggccgccact gccgcactag 13740 accgtatcgt agacgggaag gtcaacaaag tgctgatcgt cgggccaaaa cgcgttgcga 13800 aagtgggctg gccaagcgaa ttcgaggaat gggggcacct ctgtttctgg aagatatcgg 13860 tcatcgacgg tgatgcagcg caacgcgagc gcgccgcacg cgaggactgc catttctaca 13920 cggtgagcgt ggataacctc gcgtggctgt gtacgctgtt caaaaagaaa tggccatacg 13980 acatggttat cctggacgag tccagcatgt tcaagtcgca tacctcgcaa cggttcaagc 14040 tgttgcggcg ctgccggccg tacataaact acctggtgga gctgactgcc acccctgccg 14100 ccgaagggta catgggcatt ttcgcacaga cgtacctgct ggacgaaggc gagcgatttg 14160 gcaccacgat caccgggtat caggaaaact atttcatcca gaacaagtac aacttcaagt 14220 tcaagttacg caatggcgcc gaggaagaaa tcatccgtaa gatctccgac atcgtcatgg 14280 tgatgaaggc ggaagattat ctagacgtcg aaaagccaac gctggtaccg ctaccggtag 14340 aactagaccc gcattccgcg gacctgtacc gccagatgga agaagaatcc cttgtcgaaa 14400 tcatgcccga cgaattcgac gaatatctgg atgacccggt gacgattgaa gccgagcagg 14460 cggcggccct gcaggacaaa ttgctgcaac tggcgtccgg atttatctac gataccaaaa 14520 ttgtcgggat caccagtgac gacaaagtag tgaagcagaa agatgcttat cgaattcacg 14580 acctgaaatt cgatgcgctg gaagagttac ttgacagcac cctggagggg gaaaacgtct 14640 ttctggccta tcactttaag ccgaccctgg cccgcctgca ggagcggttc gggaaaaggg 14700 gtctggtcgt catggatgat gacggcaagg cgattaagaa gtggaacgcc ggaaagataa 14760 agctgctggc agcacacccc cagtccgccg gccatgggct taacctgcag cacggtggtc 14820 acatcatcgt atacgttgat aacccgtggt cgcttgaacg gtttctgcaa ttcaatggcc 14880 gcctggcgcg tcagggccag aagcacccgg taacggttta ccagatgaaa gcgatgatcc 14940 gccatccgaa aaccaaggag ctgatcgaca ctgtcgacgg caccgtcatc gaagcgctaa 15000 atactaaggg tgatgtgcaa gatgcttttt ttgatttgct aaaccgcatc aaaggccgca 15060 taactaagcg catgaaggct aagaaaacgg agctatggga tgacgaagac gactaagacc 15120 gccccgctgg cgacccgcaa tcggcgatcg aatgcgccgg acgctgatac cgaggcgatg 15180 attttccagg ggtgcaacat aacgcaactg gcgaagctgt tccgcatgga gcgccgggac 15240 atcacgccga agatcatgga tatcccgccc gtcggggagc gcggcgggta cccaatttac 15300 gccgtccacg aagtcgcgcc gtacctggta aaaccgctgt acgacgtcga gacgtatttg 15360 cgccgcatga acttcaaaga cctgcccaaa gagctgtcga aggagttctg gaacggccag 15420 cgcgcgaagc aggagtatga cctgcgcgca gggaacctgt ggccaacgga agacgtggtc 15480 agcgtattcg gcgaagcgat caaaacgctg cggatgagtc tgctgctgat ccccgacaca 15540 ttatcgcggc aggtagggct taccgaagcg cagcgcaacg tggtgcagtc atcggtggat 15600 tcaatactgg atgacctcgc gaataccctg gaaagacggt tcgcggagga agaagacgat 15660 gaagtttaaa tcgttaaacc acatcatccg gtcggtcgcc agccagctgc ggccaccaat 15720 gcgcatgacg gtcgctgagg cggccgccaa ataccgttac gtgaaccagc ccggcgcata 15780 tgtcgggcct tggcttaata tgaccacgcc atacatggtc gagccgatga acacgctgaa 15840 cagccgccat tacaacaaaa tggcgtttgt cggtccggcg cagagcggga aaacggatgc 15900 gctgatcctc aacggcatta cctattcggt gaaagtagac cccatggata tcatggtgtt 15960 ctgcccgact tctaccgccg cacgcgactt ctcaatgcga cgcgtggacc gactccatcg 16020 gcacagcccg gaagtaggcg ccatgctgat gaagaaccgt gatgccgata acaaattcga 16080 taaacactac accaccggga tcattctgac gcttagttac ccatcggtta cggaactggc 16140 ggggaggccg gtgggccgta tcatcatcac cgactatgac cgtatcgacg atgacatcgg 16200 cggcgacggt aacgcctttg acctcgcatc aaaacgtaca acgaccttcg ggtcgttcgc 16260 catgtgcgcg gcagaatcgt cgccgtcccg cccggtaaaa gacccaaact ggatcaagaa 16320 aacgccgcat gaagcgccac cgtgcgacgg catcgtcggg ctttacaacc gcggcgaccg 16380 ccggcgctgg aaatggccat gcccccattg cgaccagtat ttcgaaggaa cgttccagct 16440 gatgaagtgg gacaccaagt ccgccgatgg ccgaacgctc accaacctgg aaaaagcaga 16500 aacggccaga atggtctgcc catgctgcgg ctgcgaaatc gcgccggaag agaagtacga 16560 gatgaatttg tggggtatgt gggtaccgga aggatgtacg gtaaatgaga aagggcaact 16620 ggtcggcgag ccgattcggg cgacattcgc gtctttctgg ctgcgcggta cggcggcggc 16680 gtttatctca tggcagacgc tggtgctgaa ctacctcgat gcatccgacg actatgagcg 16740 cacgatgtcg gaagagtcgt tgaaaaagtt ctggaacaac gacatgggag aaccctatgt 16800 gccgaagtcg atcgagtcgg ttcgtgttcc ggaaatgctg aaagcccggg cagagccgtg 16860 ggcggaaaaa acggtcccgc ccgccgtacg ttttttggcg gcgacggtgg acgtccagaa 16920 acatcgcttt gaggtggcgg tattcggcgt ggcgccgggg tacccgttcg atatttacct 16980 gattgaccgg ttcaacatca tcaaatcaga gcgtctcgat atagacggcg agcgggagaa 17040 gttaagcccg gcggcgtacc tggaggactg ggatttgatc gagaagcagg tcatgatgaa 17100 gacctatccg ctggccgatg accccagtcg cgtgatgcag gtcaagatga cagcctgtga 17160 ctccggcggt gcagcaggcg taacggccaa tgcgtacgag tattatcgca agctgcgccg 17220 cgaggggaaa aacgggcgat tcatcctggt caaaggcgac cctatgccga aaagcccgcg 17280 tacccatatc gcgacaccgg actctaaccg gaaggacaaa aacgcgatcg cgcgcggcga 17340 cgttccggtg ctgatgataa actccaacat ggtgaaagac atgcttaacg gccgactgga 17400 tgtaacggtt cccggaaaag gcatgtatca tttccctacg tggcttccgg actacgcata 17460 cggcgagatg tgcgccgagc atcgcgacga aaaaggctgg caatgcccgc agggtacccg 17520 aaatgaaacg tgggacttga gttactatct gatcgggatg tgtatcagcg ggcgtgtcct 17580 cgcgatggaa gcaatagact gggataaccc gccagtctgg gctgacgagt gggataaaaa 17640 cccgctggtg gtcacaatag ataaacagga ggccatcgca gaaaaaccag atacaggtta 17700 tagttttgcg caactggccg aaatgttagc atgaggatga ccaccatgac cccagatgaa 17760 tgccgagcca agtaccaaca atggctgaat gacgctatgg acgcctataa ccagctgaac 17820 gtcggtggtt cggtgcgtgt tgtggtggac cagaacggcg aacgcgtaga gtatacggcg 17880 gccaaccgcc agagcctgtg ggcgtatatt ctgcgactgc agaacgcaat taactcaccc 17940 gacccgtgca gagccttctt cggcacgccg agtcgcccag cgaggtttat tttctgatga 18000 gcgaagtcaa gaaagccact cgcgcgagca agaaaaccgc ggttgctacg gtcgacgcct 18060 ctccggcgaa acctgcagcg ggcggcggcc ttgagggtgc tgaacgaaac acccgcgcaa 18120 ccttcaactg gaatcctgcg ataatttcgc cagaccagca gatcgcccgc gataaggata 18180 tggccgatgc ccgcgcacag gacatggtgc agaacgacgg ctatgccttt ggcgccgtgg 18240 cgatccaccg tgacagtatt gtcgggtcac agtacaagct gaacgccaag ccgaattccc 18300 tgatacttgg cgctcctgac ggttgggcgg aggaattcca ggctatcgtt gaatcgcggt 18360 tcaacatggc ggccgagtca ccggaaaact ggttcgacgc ccggcgcgtc aatacgttta 18420 ccggcctggt tcgcctcgcg gtcggcggat ttttgatgac cggggaagtg ctggggtccg 18480 ccgagtgggt caagtctacc ggacgtggcg cattaggccg ccggccattc ggtaccgcca 18540 ttcagtttat ctcgccctac cgactgtcga acccggacat gcagacggat accgaccgga 18600 tccgtaaggg cgtcgagatt gacgagtatg gcgccccgca ggcgtactgg ttccgcgaag 18660 ccttcccggg agactacacc aacattgaag gccagtggcg ctggaagcgc gagcctgcgc 18720 gattcgactg gggccgccgg cgtattatcc acatcatcga acagctgctg cccgggcaga 18780 cccgcgggat cagcgagatg gtgtcggcgt tgaagcagat gcggatgacc cgtaatttcc 18840 aggaagtcac cctgcagaac gccatcgtta acgcgacgta tgccgccgtt atcgaatccg 18900 aattgccgac gcatgaagtc ttctcgcagc tgggcatggg gcagaccgcc ttttcggaat 18960 acttcaacgc ctacatggcg agtatggccg agtatgtcgc cgcgtcgaag aacatcacga 19020 tcgacggcgt taaagtcccg cacctctttc ccggaacgaa gttcaacctg aaacccgccg 19080 gcacaccggg cggcgtcggt actgactatg aagaatcgct gctgcgcaat atcgccgcgg 19140 cgctcggtct ttcctatgag cagttcagcc gcgactacac gaagacgaac tacagttctg 19200 cgcgtgcgtc gatggcggaa acgtggaaat tcatggagag ccgtaagaag ctggtagccg 19260 accgtttcgc gtctatggtc tatacgctat ggctggaaga agagattaac gccggcaatg 19320 tgccgctgcc accgggcaag acctggcgtg acttttacga cccgatgttc cgtgatgcga 19380 tttgcaatgc tgaatggatc ggagccagcc gtggccagat tgacgagaag aaagaaaccg 19440 aagctgcgat cctgcgtatc aagaatggcc tgtcgacata cgaagccgaa attgcgcgcc 19500 tgggtggcga tttccgttcg gtgtttgagc agcgcgcgcg ggaagaaaat ctgattaaat 19560 cgctggattt ggatttttca ggtaaagttg tcgaaggcgc agagacgaca tcatcttcct 19620 cgtcggcgac cgataaccct gataaggaac agaaccaatg aatgcacatg ttcgatccag 19680 cttaatgcaa gcggttcagc gcatgaacgg gtcgccggta gctgtccgtg aaagcgacac 19740 caatttcctg ctgaatatcc agtcggtgtt ccagatgagc gccgacgagg acgactttga 19800 cctcgatgcc gaagaacgta tcgccacgga gcgcaatcgc aatctatgcg cggcttacgg 19860 catggcaccg tcgagcggaa ataaaccttt cgccttttcc ggcggcttcg ccatcatccc 19920 gatccacggc tccctgatta accgctatgg cggctattac tatggctacg tgacgggata 19980 caatttcatc cgctcgcaga tgaacgccgc actggcagat cctgacgtgg aagctattat 20040 tttcgacgtg aactctaacg gcggcgaagc agcgggctgt tttgagctgg cgaacgagat 20100 tttcgcatcc cgcgcagtga agccgtcatt cgctgtcgtg gactccaatg cgtactctgc 20160 ggcttacgcc ctgggcagcg cagcgacgaa aatggcggtc attccgtcgg gcggcgccgg 20220 gtccatcggg gttatctcga tgcacgtcga tatcagtaag atgttggaag acttcggcgt 20280 taaggttagt attattaaat ccggtgcgca caaagccgac ggcaacccgt tcgaatcgct 20340 ttccgatgag acaaaagccc gctggcaggc agatgtcgac accatgcgtg aagacttcgt 20400 caatcttgtc gcacaaaacc gaaatttaga tccgaaagtc gtgcgtgaca ccgaggcatt 20460 atgctataac gccccagaag cactggccct cggactaata gatgcggtca caacgccggc 20520 taaggcagtg gctgaattcc taaacgggcc gtccggtggc tcggatgaac aaccaggagc 20580 aaacgcgatg tttacccaag aacaaatgga cgctgcccgt caagatgcag cagccgaagc 20640 aactgccacg gctaccgcgg cagcgactac ggcggaacgt aatcgcattt ccggtattct 20700 gggatgcgaa gcggcgaaag gccgttcaaa actggcgtca catattgcgt tcaacaccgc 20760 aatgagtgtt gccgatgctg aaaccatgct gggcgcttct gcggtcgagc aggccccggc 20820 atccgcagcg gctaccaatc agccggagaa aggggcagac agcccgttca agacggtgat 20880 ggataacgct gaccacccga atatgggtgc ggaaaacgaa cagcaggctg aacccggcaa 20940 aggtgatggc ctgatggctg cgatggccgc tgtagctggc gactcgttca ctaagtaaga 21000 ggcgactaac atgtctttga tctccctgat ggcaagcctc ccgaactatc tcgctggcaa 21060 cggcgacctt ggttcgtggg aacccactca gctgtttgct ggtgaagctg atatcgtaac 21120 cgacggcggt gaagtcgcag tcgcgtttgc gcgttatcag gtcatcgcca aaaacgcagc 21180 tggcaaactg gtgccttatg acccgaccac tccggccaac ccggaagcga cggccatcgg 21240 tatcgctaac gaagctggtg tcgtgggaac ctacgcaccg tattacatcg gtggtgtgtt 21300 caaccacgaa gcactcgtat ggccagcagc agtcgacact ctgctgaaac gtcaggcggt 21360 gttcgaacgt acgaacatcc acatcggcaa cctgtactaa ggagcagcag aaatggctgg 21420 attgtacgaa actaccgtcc tgatgggagt gcaacgcaag gttaagtccc tgccggcgtt 21480 cttcctgcag tggttcccgc gccagattaa cttcgaggaa gaccagatcg cgttcgataa 21540 ggtcatccag gacgttaccc gcgtcgcgcc gtttgtcgca cctaccgcgc aaggccgtgt 21600 gatcaaggaa caaggttaca acaccaagac cttcaaaccg gcttacgtta aaccgaagca 21660 cgtcattgac ccgaacatga tcgttccgcg tcaacccggc gaagcgctcg gtaccggtag 21720 cctctctaac gagcagcgtc gtgaccgtgt tatcgcattc ctgctgatga agcaccgcgc 21780 gatgcatgaa aacacctggg agtggatggc cgcgcaggct gcgcagtacg gctatgttga 21840 cgtggaaggg caggattacc cgaaaacccg cgtagacttt ggccgtgatg cggcgctgac 21900 catgacttcc gactggaccg ccaccggcgt taccctgatg gacatgatcg ccgacctgcg 21960 cgatggccag cgtctggtgt ccgataagtc actttccggc acggtgatcc gcgattacgt 22020 gttcggcggc gacgcatggg accagttcgt taaagtcggc ggcgcagagc tgtggggcaa 22080 agacggcctg atggatggca atatccgcgg ttccgactcc aacctgaccc gtctgtggga 22140 cgatgtcgaa ggtgttcagc tcatgggtga actggtaggc atcaacggcg ccggccgtat 22200 gcgtttctgg gttaacactc agaaattccg cgactggaaa aatcaggaac agtacctgat 22260 gaaccagaag gccgtcatgg gcatctcgtc tgcgattgaa ggcgttaagt gcttcggtgc 22320 aatcatggat aaagcggccg gctatcgggc gctggaatac ttcccgaaaa tgtgggaaga 22380 agaggatccg agcgtggaat acctgatgac tcagggcgca ccgctgatgg tcccggcaga 22440 cccgaatgcg tcgttcctgc tgaccgtcgt tccgtaacca cctgcaggcc cgtcaataat 22500 ggcgggccaa tttaaaggac agagattatg ccacaacgta aagtagtcca gacggtcatc 22560 gttttccgcg acggccagcg tatccgcccg gcgatcggtg aaatcttcaa cttcacccag 22620 aaagagctgg aatccatcaa cagcatgaac ccgggcgccc ttgaccgtcc tgtcatcgaa 22680 gtcgatgcgg aagagcaggc ggcgaaagag aaagcgcctg cgcaggaaga aaagtctgac 22740 gcgaaagcca ccaccaaaaa aggcggtaag gccggcgcag cggacgaaga ggtctgatat 22800 ggcctctaac ttcgcggcaa tcaaagcgaa ggcacgcagg gacgttcacg cgtccctgtc 22860 tgtatctgcg cggtatgaaa gctattcgca ggaagtcatc gtcgacggtc ttagcgtgcg 22920 ctggcacaac aagcagcaac tggtcggcga tctggatagt ggcggttacg cccagattat 22980 cgatggcatc gagcgaatcg tttttatgca ggacgagctg caggagaaag gcgtcacgct 23040 ggaaggcggt gatgtgatta tcatcacggc ggaaggatac ggcaacgttg gcctggtgct 23100 acagacgcag gaaccgattg tcggtccggt cgaagtgatc tggcaggtgt cgaggaagaa 23160 ctgatgaccg ttaacgttat ttccgtgggc gacctggagc tgcgtgacta tctcaagcgg 23220 cttccggaaa taaccgaact ggcgatgcag atggccatta acaccgtcgc atcgcgcacc 23280 ggcatgtcgt tggtcaagaa aaacatgctg aacgaggtgg ccttcccatc cgggtatctc 23340 aaccccgacc gcctgaaagt caccaagcgc gccaccagaa ccaacctcga agccaccatc 23400 accggacgta aacgggcgac ctccctggcc cggttcgtga cgagtaacag tgttgtgaac 23460 agccggcgaa aggaaggggt atccgttcga gtgaagcgcg gtaagaccac gtacctgaaa 23520 aacgcctttc tcgtcaggct gaaaaaaggc gccagtcttt ccgaagacaa ctacaacatc 23580 ggccttgccg taaggctttc cgccggggag tcattatcga ataagcggac gcagcataaa 23640 tcatggctgg ttccgggcaa ggtggcgttg ctgtatggcc cttcggtaga ccaggtattc 23700 tcggaggtgg ccgagaaggt cgggtcgcaa attgctgaca tggtggcgac ggagtttttc 23760 cgtaatttcg agaggttatc atgagtaagc gcctcgatgt gctgaaagca ttaacggatt 23820 tcctggaagg catttccccg gataacgggt atccgtatga cttccgggga aaggtgtacc 23880 gcggtcggga ccgtttcggc gcggaatacg tggcaaagat gccgttcctg tctattctgg 23940 aagcgaaagc aaccgactac gggaagttcg ctaacgagga acagaccgtc cggatggatg 24000 actgggtgct gctggttcag gggtggtgcg cagatgacgc gcgcaaccca acggacccga 24060 tttacgacat cgtggcagtc gttgaaaagc gcctgtcaat gctcatctcg aaggatgaaa 24120 atggaaaccc ggaattcccg ggggtctatc ggttaaaggg aatgattgct acactgacac 24180 tcgcacagcc ggttgttcgt ccgcccgagg aaggactatc ggacacggcg tttttcttcc 24240 tgcctattag ggtaggacta aaagtagata ttcggaatcc ctaacaggag atgaaagatg 24300 caaagcgatt tccagaacga ctatacgatc ggacgtggga aaacctattt cgataagttc 24360 ttgccgaact ctaaccgcaa gactggcgaa atgtacttcg gcaacggccc ggaattcacg 24420 atcaccactg atacggaaaa cctggaccac tatgcgtcgg attacggcct gcgcgtaaaa 24480 gatgcctccg tcctgctgga agccggcatg accgggactt tcacctgcga caacatcgcg 24540 gcggagaacc tggcgctgtg gttccttggc gacctggtta acatgaccct gaccgaccag 24600 accggcgtca aggaagtgtt caagccggta ctgcgcggta agtattacca gatcggtacc 24660 agcgacgaca cccctaccgg cctgttcaac gtggataacg ttgtggtcgg cgtggcggat 24720 ggtgacgctg aaatcgtccc gggaaccggc gatattagcg gcctggcagg cgtgaccatc 24780 gttaccgccg ctggcaacta cgagctggac ctggcgcaag gccgtatcta catcgagccg 24840 gactccaccg agttcgcggg taacaagcag atgatcatcc agtgcgatat cgctgcgcag 24900 aaccgcaaca tggtgatcgg caagaccaat cagatttacg gcgccctgcg ttacatcgcg 24960 gacaacccgg tcggtaccaa caaaaactac tacttcccga aagtggcgct gcgcccggac 25020 ggggattatg cgctgaaagg cgacgactgg aacgtgatgt cgttctcgtt cgaagcgctg 25080 cagctgaaca acctcaccca gcgtctgtac attgacgtgc tgccgtctgc ggcaaccgtt 25140 gacccgacga cgctgcgtac cgtgtctgta tcgctggcga gcacttcggc ggcgtccggc 25200 ggtgcgggta tcgtggctac cgctacggtt cgtgacggca acggcaccgt ggttcagggt 25260 gaaaccgtga acttcacgac ggacaccggc gctaccgtta ccccggcgag cgcgtccacc 25320 gcgagcacgg gcctggcaac caccacgctg aaccgcgcga cggccggtac cgccaaagtt 25380 accgcaacgc tggcgaacgg caagtccgca gtatcgcaaa ctgcgacctt ctcgtaagag 25440 cagaccgcag tcacaccgga aagcgcctac gggcgctttt cttttatgct tttctgccga 25500 cgtgctacat taacgacgtc aaccaacgaa gaggataaac cccatgtcac tgtcagattt 25560 caccccggat accgaagaaa tcatcgttaa gcgcgctaaa aaaggcgata tgacattcga 25620 ggtccgcggc ctttccttcc aggacatttc gaagatcgtc cgcgtgcatt atgacgacct 25680 ggaagggctg tttgatattt acgaaaccca cggcggcggc gacctttcct acgtggccat 25740 gggcaaattc gccatgggtc tgattaacga tgcgcccggc ctggtagcgc acatcatcgc 25800 gctggcggca gacgacgaag ccaacctgga gaaagcccag cgcctgccgc tgaccgccca 25860 gattgacgcg ctgaaagccg ttggccgcct gaccttctcg gacgttgaag atataaaaaa 25920 gatgctacga aaggccatgg acctgatgag ggaaacaaag gcaagccgga cacccgcgtc 25980 tacagcaaaa gggaaaaagt aatccggttt cacaacgagc tgcgggaagg cgtgtccttc 26040 ctgatgtctc agggacaccc agacgcacgc cggtacccgc tggggtacct gtggtctgaa 26100 atcaagattg cccggcgccg cgtgaatatg cacctggtga cggaaagcac gttactgcag 26160 gcgctactgg cctccgtcat gaacgggaag aaaggtggcc cgcactacaa aaaactgatt 26220 aagggcttga gcgatggcta acagcaaaga cgtcgaacta aggatccggg cgagggattt 26280 cagccagaaa cccctgaaag ccgtggcctc cgcgattgaa gcaatggcga aggcgcagga 26340 cgaccagcgt aaagcggcgg aacggggaga agtctcgacg cgtcagctgg aagcctcgta 26400 caaaaaactt gagcaggccg ggcagcagct gttaaagctg aatgccctgg tggagctgta 26460 caaacgccag aacgccacga tggttgaagc ggcgcaaaag acggaagact tacgggccaa 26520 gcaggcgcag ttgcagcaag cgtatgattc atccacgaag gtaactaaaa aacaggaagc 26580 cgaacttgcc cgtatcaacc gtcaggttga gcgcgcagaa cgcgccgagg cgtcacgcgc 26640 cgcgcaggtg agccggacta ccaaagaact gcagcgatac ggtattgaga cgaaaaacct 26700 tggtgccgcg cagtccagca tcgttaacag cgtggcgagc gttaacaagg tactgcagca 26760 gcaggaaaac atcatcgcta ccgcgcctgc ggcggccgcc caaaataaag tcatacaggg 26820 actgcagcag caagcgcagc aggcactggc ggcggcaaaa gggtattcaa ccctgggccg 26880 ggtcgtacag accaccacgt cgcagatggg gccactggcg tcgcaaatcc agcaaatcgt 26940 aagcccgtca gacgctgcgc gccggacgct gtctggactg cagcagcagg tgacaaccct 27000 tgcgacggag atagcgaata gcggcaaaaa gattaccgat atcacaggga agatccgcca 27060 gctgaatgac gcgaataaaa gtgtttcggc catggcgcac cagatcgata tgtaccgtca 27120 gcaggtggca gcgatccggg cagcgcgggc ggaataccgc acagcaatgg gggcggtaca 27180 gggtttagcg cagcagatgc gaacggccac taccgacacg ggtgaattgt cggtccggat 27240 gcaggcggca cagcagagac ttgcggcggc cgcccggtca ttgcgggaca ccgggactgc 27300 tgcgcgcacg acacaatcgg ctttgcgggc ggcaggcatt gatacccgta atttgaatag 27360 cgccgagcag gcgctgatct ccacaagccg tcagaccacc agttctataa actccctaac 27420 gcaagcattg cggaataacg cgggcgccac gcgcgacggt tcaaaagcct tctctctttt 27480 ccgcgatgag ggacgaacta cgttatcaat gctgcagcgt atccgcggtg aggtcctggg 27540 gctggccacg gcctatgttg gtgtgcaggg ggcgcttaat caggcatccg gtgcggtgga 27600 tgcgtacaag atgcgtcagc aagccctggt taagatctcc accgttgttg gggaaagcca 27660 ggcggcactt aacgacgaat ggcaatatat gctcgggctt tccgacaagc tgggtattga 27720 tatcggagtg gtcgcgaact cgtatacccg gttcgcggta gcggcgaaag ccgtcggtct 27780 gtcgttgcag gattcaaaat tcatattcga aagcgtggcg aaagccggcc gtgttttcca 27840 cctctccgcg gatgacatga acggtatttt ccgcgcactg gaacagatgc tgtcgaaagg 27900 gcaggtttac gccgaagaac tgcgcggcca gctgggcgaa cgtttacccg gggcggtggc 27960 gctgttcgcg aaaggtatga acatgaccac gacgcagctg atgaaggcaa tggagaacgg 28020 cgaggtttcc ggcgaagcgg ttatcaactt cgcccgtgaa caggctaagg ctattgatgc 28080 ccagctggaa accgcgagca aaggcgtgga cgcgatggaa gcccgcgcac gtaacgcgat 28140 gaatgcattc cagctggcgt tagcggactc cggatatatc gatgcatacg ttcagctgct 28200 gcagaaggtc acggacttcc ttaatagctc ggatgggagg gaggccgcgg taaaactggg 28260 tgcggcattc agctacgtgg cggacactct agggtatctg attgacaacc tggacacggt 28320 tatcacggtg ctcggcgttc tggccggcct taaaatcacg cggatggttc tggggttagt 28380 cgggtccatc cgcacgatgt tgccgatgct gaaagaaggc gtcgttctca tccgcggggt 28440 atacactggc cttatgacat gggcgaccgg tcttgcgacg gttgaaggcg cggtcggact 28500 tctcggcgtc gcgttacgcg ggctgctgcg cgttatcccg tttgttggcg cagcgcttat 28560 cgcgtacgac atcgggtcga tcatgtacga ccagtcgtcg accttccggc agggcgttga 28620 cgaggtcatc cgggattaca aaaacctcgg caatcagctg ctggcggtcg gggagtccat 28680 cccgacgatg ctgtacgaca tcctgatcgg ctgggtacga cccgtaacga cgcaattcgc 28740 cacggccacg aagatgatca tgggttggat tgccaatgtg ttgcgcctga tccccggtgt 28800 cggcgaaacg ctggcgaact gggcggatac cctggccgaa gacatgacca aagagcaccg 28860 tgacttcctg gagtccacgg gcaaggtctg ggatgacgtc gataaaaaat gggccgagtt 28920 aaataaaaac atggtcgaca ccaacaagac tgcggtggat gttatccgtg gtcaggtggc 28980 gatgctgatg gccgatatta aggcgatcac aaaccctcaa ttccagtaca ccgctgaccc 29040 ggaaactgga gtcacccagc gcgaccgcga catcaaaggc atgacgaaag accttgccaa 29100 gatggaagaa caggcgaaaa aggctggcgt tgccgcgcag aaagcactgc agcgtaaaaa 29160 cctgccaggc cgcctggcga ttatcgatga ggaatttgcg ccgcagtacg cccgtgccaa 29220 gtcgatcggc ggtgacgaag gtgctgcgat gaccaagcgt ctcgacgcta ttgtggctgc 29280 gcggaagaaa gccgagacgg attcctataa cgccatggaa aacggcagca agggcagggc 29340 gaacgcggcg aagcgggagg aaaacgcgct ggcggcgctg acctctcagt atgaaaaact 29400 ggatgatgcc gttggcgtca agcagtcgaa ggtcgacccg aatgcctcgt ttgatgaccg 29460 actgcaggcc aaactgcagg ccgttaatac ccagtacgac cagctgatcg ccaaggcgaa 29520 aaaactcggt tcgggcgggg cagaactggc cggcaagttt gaagacctgc gcaagcggaa 29580 tctcgaatat gctaccacgc aggcgaagct ggaagagatc aagcgcgtgg aggaccagct 29640 taacgcggtc caggaaacga agaaaagcct gctggatgag ataaacgcca aacgtcaggc 29700 gggcattatc tccgaagatg aggcggtgaa gcagacgtcc gagctgtatg cgacgatgaa 29760 cgtgaacctg cagcagtcgg cgaacacact ggaccagctg gcgcagaaat tccgcaatgt 29820 tatgtcgccg gaagactatg cggcgctcat ggccaaaatt gcgcagatcc gcgcgggcct 29880 gaatgacgtc accggtacct ttacccagat ggatagtacg gtggtgcagg gcgttctgga 29940 tgggctggcg acgggtctac agtcggtcac ggatagcctt gtccaagtcc ttagtggcac 30000 gatgtccctg caggacgcat tccggagcct cggcgctacc gttaccaagt tcttcgcgga 30060 cttcctgatg aagattgcgc aggcgatcct gcagcagatg gtactaaact ccctggcggg 30120 aatgggcggc ggtatcggtg cagcagcggc atcgcttggc ggtgtagcag cgaaacacaa 30180 cggcggcatg gtcggcagca aaacgacggg cggccagcag cggaaaaact ccgtcagccc 30240 gtcgttgttt gtcggggcgc cgcgcttcca tgacggcggc ctgcccgggc ttaaatcgga 30300 cgaggtgcca atcatcgcgc agaaaggcga acagatcctg tccaaagacg acccgaataa 30360 tataatgaac caggggggcg gtagcggcag tggttccggg tcatctaatc tgcaggatat 30420 cagggtcatc aatgcgatag attcggcatc ggttgtcgcc gccgggctaa gtgctccgga 30480 aaatagtaaa gtggtcctca acttcatcaa ggccaataaa caggctgtta aacaaattct 30540 ggggtgatga atggcgagct taaccgacaa tgatgcactg gtcagcagtg atgggctggt 30600 agcgcacagc cttacggatt cgacgactga cgcatcgggc attaatccgg cggcgggaac 30660 gtcgtcggaa cagttccgga tggtgaccgg acttctgcgg gcgcaccgta ttgctccccg 30720 cccggcggcg gtacaactgg caaatcgcat cctgactgca gctgtatcct acctctaccg 30780 tggccagtcg tcagaagccg ggacgtttat cccacactat ctcgtcggcg tccgccataa 30840 cttcacgttg ggtaatggcg acgtggtgca gcccggagac gcataccgta tcgccccgac 30900 ggtggagatt gagccgagta ccgataccga ctcggaaaac catgctttcc gtgatgcgta 30960 tgaagccttc tcgatcggct ccgacgtaat gggggagaac gcctggacgc tcgcaaagga 31020 cgctaccgag cgccagatta aagggtcgat tcgatactcc gggttgtggt atacgccggg 31080 cgcggtaccg gtcattacgc agttcactcc gaatgataat gggtggcggc cgccggcgta 31140 cgttggtcgg cagatagggg cgcagtgggc gtcattcggg gatgcggaag ccaccgacaa 31200 taccgtgttc atgatgaacg acgcacagga cgcatggacc gcgcagaccg gaaaaatcga 31260 tggccttttc atgccggtgt tctacttcga ctctcccggg tcgacctcgt acggcccggc 31320 gaacacgttt gggtggaatg gccccttcga ctcacagagc atgtacgaac agctgtcggc 31380 gatgcgggat gccgttcgca tcgctacaca ggcaggcgag gcgggccgta aagcctacgc 31440 aacggctatc gctacccgtg cgcttaaatg gttcgggaat gaccgcaact ggatcccgtc 31500 gaacccgggc atcgcagacg cctggagcgc ggcgatccgc aaagcggccg ttctggggta 31560 ccaggagggg gataccgtta cgctgcctga actctggttc accgtcccga atcgcctgaa 31620 taccgatggc tcattcccga cgcctgtcta tgagccgggg ctactggcgg tggcgctgca 31680 ggcggcgatc gcggtggata agctgcagcg gccaaacaat gccgcaggtt cgctgtctac 31740 cgaagtggcg cgcgtggtag aaaagtgcat ccagatgttc gacttcacct acgtgaccag 31800 cggagtaatg gccggcacat tcagcccgga cccggcgaac cttaaatggc aagggcgctg 31860 gcatgcggaa ctgctgaatg ccatggtgga cctgtatgac tggtgtgggc agtcgaacaa 31920 taactacacc gccacgcggg cgaaggcgcg agagtggatt acggggctac tggactcggc 31980 ggaagcgcta tcggcagacc agtctggcgg attcatctat ggtcggtcta tgtggccgct 32040 gcagccaaac tggaaagacg gcatgacgga gtcgttcgaa ttttccacgc agatcatcac 32100 ggcggccagt ggcaaagagc agcgcttgtc ccgtcgcacc aaaccgcgcc gggcgctgtc 32160 catgcgccat acgctgacga cggcagacga ggcggcgcag tatcaggcca tcctccggaa 32220 gcgccagtgg cggccaatgc ttgttccgca gtggcacatg gcatcccgca cgctggtagc 32280 cgggaaagtc ggcgatacca ccctggtcct ggacaaagag ccgccggcca cctggggtgt 32340 ggtgaaagcg ctgtacctcg tatcagggga tgaccgccag ctgcttaacg tgctgcgggt 32400 atccgggtcg acggttatgc tgcgcgattc gctgacgttc ccggtaccgc gagggtcaga 32460 tattatgccg gtgcagtacg ggctgctgaa taacgacctg tcgtcttccc gggcgatctc 32520 caccacgatc gaagcgcagg tcggtttcac gatcctgccg cagacggact cgtttaccgt 32580 gccggcggta tcatcgtaca acgacctgat ttcgtttatc gcggaacagg gccatcgctg 32640 ggcgaaatat atccgacggg ccgccgcgct tgatcccgca gtatggccga cgtggccgcc 32700 aatgccgtcg aactatacga cgcgaatgac ctttgaactg aacggcgata cccgcatggt 32760 catcacccgt aaacctaact gggtatccgc ggtgacagtg gccgacgcct ggcagtacga 32820 cctgatcgac tattacaact cggcggttac gccggggtat gcggagaacg ccggacgccg 32880 tacattccag gcgcagtgga ccgcattcac gtatgatgag gttatcgata tcctcgcggt 32940 attctacgcg ctgcgtggta cgcaggtggc ctgctgggta ccatcgtggt cccacgacct 33000 gacggcggca gaggatatgc cggcgccgaa tcagttacga gtggagcgga acgccgtcat 33060 tgacgaagaa atattgcttg acgacccgag tatcgcattg atggttgaaa cgtttgatgg 33120 ccgcatgtat tgcgcggcgg ctaccggggt aacaacgtca gtcggggtat cgactatcac 33180 actggaccgc gagttcctca gcccgctcaa aaaggcggac atgatgcgga tcagcctgat 33240 gtaccgtgta cggcaggcca gtgattcggt ggaactttca tggcatgccc gcggcattgc 33300 cgaattgcag acggccttca tcaccgtcca ggagtaaaac gtgtcatatc ctcaacttga 33360 agacagcgtt gacagcggga aaccgctgta tttttacgag ttcatttacg gcgatgcagc 33420 gacgaatgcg taccgttatg tcgccgcact ggacctcact atctacggcg gccgcccatg 33480 gacccctttc ccgataaagc acagcgatat cgttacatcg gggtcactgg ataagcagac 33540 gctgacggtg acggcgcggg aggatattga tattaccgga ctggtagtga cccgcgcgcc 33600 aagccgggta acgatgctga atatctaccg cggccacgct ggcgatgatg acatgcggat 33660 ggtctggacc gggcgcgtcc tgtccggcaa catgatagag tcgtccgagg tggaactggc 33720 ctgcgagtcc ataagcacat cgcagctgaa tattggtctg cggcgtaagt atcaacgcgg 33780 atgcccgcac gccctttatg gtcgggcctg ttcagctgat aaggcgttgc attcggagac 33840 cggttcgtcc acggcggtcg ctaattcaat gacggtgtcc gttaccctga cgagtgaaga 33900 ccgcgggctg accgaggcta ccctaaccgg tggtatcttc cgcatcacgt tgaagaacgg 33960 cctgaccgaa atccgggcga tctcgtctgc gataaacaac ggcggccgca actggacgtt 34020 aaatatcatc gcgcctattt ccgacatgac cgccggccgt ccggtttctg tatcaaaagg 34080 ttgcctgcat acatacgatg cgtgtaaaaa cgtgtttaac aatgcggata actatggcgg 34140 atgtgccaat atccctatca aaaacccgtt caatgcaaac cagttctagg gggcgccatg 34200 ccagattggg tcgtctatat aattatttcc atcgcgatgt cgctggccag ttacgccctg 34260 actccgcgtg caaaaacgtc cagcgctaac cagtcaccgc agacggtcga cgtgccgacg 34320 gtcgatgcgg gccggtccat ccccgtagtc ttcgggacgg tgcgggtgaa atcgcctaac 34380 ctgttatgga tgggcggaca acggacaacg gagatcaaga aatgagtgat atccgcgtat 34440 tacctactga cctgccgacg gcgggtcttt gcgttaatgg cgctcgcgac tggttcgcga 34500 aacatgggct ggacttccgg gacttcatta agaatggcac tccagtagat gtcatgcggg 34560 cgaccggttg cccactggcg gaacgtgctt gccaggccgc cgagaagcgc gtcaacggag 34620 ataactgatg ggcgggaaaa gcaagaaaaa atcggtcgtc ggctataagt acaacatcgg 34680 cctgcatttc gccatttgtc acggtccgat cgccaagctg caggaaatct ggtgggcgga 34740 taaggtcgcc tggtccggca cgttgaataa ccccggggac gagtcgcagg ggcttgtggc 34800 ggtggacaat accggcctgt ttggcgggga ttcctccgaa ggcggcgtga aagggctggt 34860 ggaaatcggc ttcggtggat gggggcagcg ctgtatcggc gttggatccg acgggtcgta 34920 ttccgcgcca gccatcctgg cctggttcat ctccaaagga tacaactgga agccgcaggt 34980 taaggtgccg gacctcggcc tgaattaccg tgggctggcg gtcgcgctga tgcatgacca 35040 ctacatcggg aacaacgcct acctgaaaga cgtgtcgttc aaggtcagct gcttctgggc 35100 cgactggcac cctgaacttt gctacatcgg cgataacatg aacccggcgc acatcatccg 35160 cgaaggactg gtgaacacgg aatggggtct gggatacgcg ccagccacga tcgatgacgc 35220 cgcatatctt tctgccgcgc agactctgta taacgagggc ttcgggctat ccttcgtctg 35280 ggatgacgac aaagacctct acaccttcat tgacgaggtg aagtcatgca ttaacgccgt 35340 gacgtatctc gatccgcgtt ccgggctatg gacgattaaa cttatccgcg ctggcgagcc 35400 atcggcgctg accatcaacc ccgacaacgc cagcctgaaa tcctttaccc ggaaagcgct 35460 gggcgaaacg tacaacgaga taagcacgaa gtacacgaac ccggaaaacg aagagtacga 35520 gacagttacc gttcaggacc cggctaacat cgaggcgcag ggccgtgttg tgtcgacgac 35580 gaaagagtat gtcggcgtgc gggatgcaaa cctggccatc cggcttaccg aacgtgacct 35640 gcaggtggcc agcgcgcagc tgtgtacagc cgaggtgacg gtgaaccgcg aagcgtgggc 35700 catcgcgccg gggatgaacg ttaccttcaa ctggccgaga cacggcatct cgaacatgat 35760 catgcgtgtc gaagaggtga gcattgctgc tgtcggggat gactcgatct ccctgcgcat 35820 cgtggaggac gtcttctcgc gctcatcggc gaccttcgcc ggctcgcagg ataacggctg 35880 ggtcgacccg gcacaaccgg caacgttgtt cccgtaccgc cattcctggg agtatccgtt 35940 ctggtatctt attcgcgctg caggtctgcc agcagacgtc ctgccgacct tcgccggatt 36000 ctcgacggag attgctaccg gcggcaacga taacgcgcaa tcggtccagc tgttctccta 36060 catcaccacg gacgctggtc catcgtggca gctggtcgca gttggaccgc tgacgccgaa 36120 atccgcgttg tccgatgcgc tggttccgga aatcacctcc ctgatgaagc tgaatacgtc 36180 ggccagctac cgcctggcgg acatggagac gaacagtttt gcgcttctca cggatggtac 36240 caacgaagag atcgtccagg tgacgaactt cgcggatgtc gcgcagcagg cgaccattac 36300 ccgcggcctg atggacacac aaccgcgtaa ctggccggcg gggaccatcg tgtacttcat 36360 cggctccagt tccttcccgg aagacgagtc agtcaggtca ttcggcgaga cggtgcaata 36420 ccggccagtg atgcagacct ccattgacca gatggacatt aataacgttc cgacggatac 36480 catcaccctg cgcgggcggt acgagttgcc gtacccggtt gccaatgtga agatcggcgg 36540 cgcatactgg ccagtgtcgg taaacgtcaa tggcattgac ctcgccgtca cctgggccaa 36600 ccgaaaccgt ctgctgcagg acgcggctac ccaggtacca tgggacgccg gaaacatcat 36660 cccggaagac ggaaccacgg tgacgatcga gctgtggcgc agcggctcaa tggtgtacca 36720 gcagcaaggc atcaccggca cgtcgtttaa catccctgtg gatgccctgt cgaccggctc 36780 ccatgagatc cgcatttaca ccgtgcgcga cggccgccgg aactatacta atttccagca 36840 cacttttaac gtcgtactcc cgtctcgcga tacggggtat ggcaatagtt acggattcac 36900 ttacggagta taaccatggc gcagaaaacg gccccgaacc tgggcatgac ctacggctgg 36960 gatttaggcg aaagcgggtg gaagcctggt atggatgcca acatgaaaaa actggatgca 37020 attgtgggcg ccgcggtgct ggccattgcg aacagtccgt cagttacgga tgacggaacg 37080 cgctacattg tcgggacgtc gccgtccggc gcctttgccg gccaggcggg gaagctggcc 37140 gtacgtgttg aaggcgcatg ggaattctat acgccccggg caggatggtc cgtttacaac 37200 ctggcgaatg gcacggcgta ccggtacact ggttctgcat ggattatccc tgcgattgcg 37260 atccccgcac agccattcct ggaagtatct ggacccggta ccgaaacctt tgataatact 37320 gcgtgggtga aagttccgct gaccgtcatc gcgtcggata cggcagacgg gtgggatgca 37380 acggccaaca ccgactacat catcccgcag gccggcatgt accagattca ggggattgtc 37440 cggcccgcgc gaaccggaag caaccctttc ccggattcaa cggcattcgc cgttggggtc 37500 ggggccacgc cggcagacgg ggatgacgtg gcatgggcgg ttagcccgga cgtggccggc 37560 gcgcagttta ccctgcaggt agccgtattg cggcgctata atgtggggga ccgagtatcg 37620 ctttttgtga aacattctgc gacttctcct gtcgctattt cgcgcgcccg cttacgtgtt 37680 ttgcgtttaa cggattaaat gcgggatgct atagtgggca aacggttaat cgagggtaac 37740 taaaatgtca gatatggacc cgttgtatga attgatgaaa gactcagcgg aggatatgtc 37800 caaggctgtg gttgaaatga aggatatgat gacggaggac caaaacaccg acgtcgtcgt 37860 cgaagggtac ggcccgaagc cttcattcag caaacagata aaagagctgg tggccgggag 37920 gtcagaaggc atatttcggc tgtatgcgac attggccgag gcccaggcgg atatcgcgaa 37980 tacccctgtg gggtctgtaa cctatgtccg gggggcggat agcacgtccc tggccgatga 38040 gtatatcaac aatggcggca ccctaactgc gaccggacgg acgatgccat ccggggtcgc 38100 cgttgagatc atgtccgcta ccgtccagcg tttaatgacg gctttgcacg ttatggcgga 38160 gggcgacgcc ggttcggttt caggtattga cagcagcgat actgtgcagg gcttgatgac 38220 cggattcaac gtactggcgg agtcctttaa taacctttca gtggaaagtc agaaaaatgc 38280 ctccggcctg tccgccctgg tctcatccgt ccagatctgc actgaagcac tgaatacgct 38340 ggcggcccgg gtcgtgaccc cagacggcgc gtcgcagtat gactatatgg cattttccac 38400 gccaggtacc gtcaacgcca gtaacgggac gttcggtagc aacacccaat accgcaggac 38460 cgggatgatc ccggttcgca agggcgacgt tgtacgcctc accgttcaca ccgcaacgac 38520 agtcgcaggc cacgccgccg cattatatga cacagcggga acgtatgtgg gtcccctggg 38580 gatcatgtgc gggacgtatg cggcgtataa ggcgcggtat taccagtgtg aaattaccca 38640 ggatggattt gttgtcgcaa acacgctgga ccagagcgcg tccccttctg cagatgtaac 38700 aggtgcgtca ctgacgattg accatcgtct tcgtggccgg gaagcagaca cggttattaa 38760 gctgacaaag tctgatttga tcccggtccg cctggataac gggaacatca acgccagttc 38820 actcacccag gacggaatcg ttaactattc caccgggctg tattcctgca ccggcggcag 38880 actcctgttc agcggtttac ctgtggcctc atctccgggc cagagcagca gcctctacaa 38940 cgtcgtgttt tatgacgccg ctaaagcgct gatcgcgtac cgccccgtgt tctccagttc 39000 gggctatgtg gttatccccg aaaatgccgc gtactgggcg cagcagataa tcaccgacag 39060 aacacccaac tggtccgagg tctcgatagt ttattacaac tacgtctaca aggatgagtt 39120 gcataagcta ctgtcatcag aacgtgagcg cctcggacgt aactacccta acgaatattg 39180 gctgcaggat ttcagcggca ctaccgatat tgagtggatc cagaacgcaa tggactgggt 39240 gcatgatgct ggtggcgggt ggttgatact gtcatcggat tatgtgaaga aacagttcat 39300 catctccgaa gcggttatcc accgtagcaa tgtgtgggta gttctcgatg gtgtcgagat 39360 taaactgcag gatggcgtgc atgacaatct gtttcgtgct gccggggtta ttgtcaatcc 39420 tgacgacccg tttggtctgt gcctcgatct tgagataacc gacaacgttc gtctgattgg 39480 tacgggatat ccgaagttaa gtggtgccga tgtgccatat tatgccgata tccccgcagg 39540 aaccgggcca cgctactgga tcggcgacga atatggatgg cgaggtacgg ggctgattta 39600 ttatggtacg cagaattttg agatcggtgg ttttaaactc cagaacgtaa aaaactgggg 39660 tactgatttc gggtacggtt ctaaaaatgg ctatatccac gatatcgacc tgtggcagcc 39720 gaacaaaaac ggcgacggca tccacttcac taacggggcc agtcatatgc gcgtccgtca 39780 gattttcggc tatgcgcgcg atgactgcct agctatggtt aatagcgacg actccctggt 39840 ttacggcccg gacaaagtcc cgacaccggg gtcaattcgc cagtggatct accctacatg 39900 tccattctgg tatggttggg cgggaaatga ggccgtgggg accagtaacg acatccacga 39960 tatcgttgct acgaatatcg ggttaaccgg taacgagcag gtcagcacca ttctgaccac 40020 gcagtttaaa atctacaacg tgacaatcag cggtatcagc agcgtcaact atatgactcc 40080 aggccggggc tgggatgaag ttaatgcgat tctgaaatcg tatgcggcat ttggtgacgg 40140 ctccaggtat caggcaggaa atgtcagtaa catccgcatt aataacatca ttgagtgcgc 40200 atcaaaaaat tacagtatcg atataacgct ggaagggcgg gatatccgca tcaaccggta 40260 tatgaaactg gacacccgtg cgaaaacaaa aggcgcgctg aagatcagca gctcggcggc 40320 cccgtatgtg acaacctcta acatcgtgga ataagcagat gactatattg attcaggatt 40380 cattacgtcg cgccgttgaa gcggcctccc gcggtgcgca gactgtgctt tacacccggt 40440 cgggcgaccc gtcgtttgtg aatatcatcc ccaagtttga cgtcagcacg attgatgcct 40500 cgttggggtc tggaacgcat ccggcattta tcgttaacgg caccgaggtt agtcagattt 40560 tcgtcggcac ctaccccggc tgtattgtta acggccaact gctgtccctt ccggaccgga 40620 tacccgccac gtcggtggcc tatgatacgg gcatcggtct cgcccgggcg gccggcatcg 40680 gctggcacgc catgacaaac gcggaatggg cggcaatcgc tttgttgtgc tatgcacagg 40740 ggcaatcacc gcgcggcaat accaaccggg ggctgtcatc ggataacccc agcgagaagg 40800 ggcggcgggc agacgggctg gccgccggga ccgaatccgg aacgggtctg acgctgaccg 40860 gctccggtcc tgtcagctgg cggcacaacc gcgactatgc aggcattgca gacctggcag 40920 gcaacatttg ggagaccgtt accggggtcc gtttctgcgg tggcgagctg cagataatgg 40980 tcaataacga cgccgcgctt tacaccaccg accacacgtt atcctcaacg gcatggaaag 41040 ccgttagtgg tgtggatggg tctcttctta cgccgactgg caccggaacg ccgggaacag 41100 gttcatatgt tccaaccaca cctaactcag ttcgtatcgg cctttcgggg accgggaatt 41160 acacactgat ttatggtgaa aatacgctgt tcaccagtgc cacgaacccc ggggctacgc 41220 cggtatccga tgtcgcgcta agggtgctgc gccgactgat gttgttcccg ctgccgggtc 41280 tgatttccga cgacgcctta tcgtataaag cgggcgggga ggtcatgaca ctccgcggcg 41340 gggcgtatac caacggggct ggcgggggca tcaacgcgct actcgctaac cgtggacgta 41400 cttcagttgg tcgatctaac tctggtgtcc gtcctgttta ctacaagcct tgacattaat 41460 gcgccatacg gcgcatttct ttcctctttc ccggcgtggt gacagaagat gtttatgagg 41520 attagcttta aaaagtcgaa atggtccctc ttgttattta ttaaactgat caccgtggca 41580 gtattgacgc atttgttcgg tatcgggtgg gggcttctgg ctgtcgcggt ggtggagtct 41640 cttccatcca tcgagattaa gaggtcgatg tgaccgccgg gggtaagggg gccgccagac 41700 aaggcgcggg acccggtttt ttgttgacat caatagtgga actttccacc ggaaatgtcc 41760 agaatagtcc gaagcgatcc gctaccccga ctacaggaat attcatatga ctgaaccagt 41820 tatcaccggt accacgttga cgactgcggc tgccgtggtt ggcgccaccg gctggtgggc 41880 cggacttgac ccgggagtcg ctatcggggc tttctggggg gctatcttct ttgtcctgtc 41940 ttccaaggaa ttaacattaa ttgcgaaaac cggattcggg ggagtaagtt tctttttcgg 42000 aattatctgc gcgaattggg cggctgaatt gctaacatgg ggcgtacata agtttgcgtc 42060 aggcgccagc gatgcacccg ccgcaatggg ggccttcatt gcggccgccg tggcgatcca 42120 aaccctcatg gccatcacga cgaaagattt caccaaggcg ttgctcgacc ggttcctggc 42180 atggctgaaa agcgcgctgg tgaagactga tatcggagga ccgaaataat gtctgccttc 42240 gcattttcgg ataccatcat cacgaccttg ccggatagcc cggcattcct tttcatcacc 42300 catacattcg ctattttcaa cgttcttctc tgcctgtcta tcgtgtggcg gctgttcact 42360 ttccagcgga aaggggcgcg ccaccgttta gcaggcggcg tgatcgccat gttgctgatg 42420 gtcttttaca tgtggacacc gttccagttc gtgctgggac gcgtggccat tgtggactgg 42480 gcgaccgtcg gtattaactg catcgtcttc atcgcgatat tccgggcgcg gggaaatgtg 42540 atgcaactat tcaagtcgtg agggggcagc actatgtcgc tatcggatga cgagtaccag 42600 aaggccgcgg cgaagatcgg aatcagtgta cctgcgctgc gggcattcgc ggaagtggaa 42660 agcaatggca gcggctttat cgatggcaaa cggccaaaag ttcagtatga gccgcatgtg 42720 atgtatcagc ggctgaaaga gaacctcggg gttagcgttg ctaatggtgc gctgcggaaa 42780 tggcctgacc tggtggctac caaacccggc agctatcagt cgctgaacaa ggaagatcag 42840 gacatggacc gggcggccaa agagattgac cgcacaagcg cactggaggc cgccagctgg 42900 ggggcgtttc agattatggg ctaccactgg aagacttgcg gatacccggt gctgcaggca 42960 ttcgttaacg cgcaatactc cgaggctggg cagctggaca cactggtccg gttcctgcgt 43020 gcatcgccgg ccatcgtatc tgcggtcaaa agcaagaact ggtcgaaggc ggcgcagctg 43080 tacaatggcc cggcgtataa gaaaaacgcg tacgacgata aactggcgaa ggcatataaa 43140 aaatacgggg gtgtgtgatg cttacgccta ccgttaaaac tgtagtggcg gctatcatgg 43200 ccgccgctgt tatcttcgcc ctggtgtggc tgcataactc gctggccgag cgccactacc 43260 agcctaccat cgatagcctg aataaaacgc ttggcagcgt gaagcagcac aatgccggtc 43320 tgactgccca gctgcaggcg caaaacgctg ccatcgcgtc tatggcggta cagagcgaga 43380 aagataagca acgtatcgcc gaactggaga aagccgcgca gcggggcgct ggcgaggaat 43440 acggcagggc caatgaagtc ctgcaggaac gcaccaccgg ttccgacgtc tgccgggcgg 43500 ccagtgatgc cttcgacgcc gagctgcgga aggagcgggc aaaatgagaa agctgatcgt 43560 gaccatggtc atgctgcttg tcggctgttc cgcccgaacc gaaacgccgc cggccgtcgt 43620 ggaagtcaaa gtgccggtgc tgcagaagtg cgatatccgc cagcctgacg cgccggcgtt 43680 cgcggtggac gcattacctg tcggtgcgcc gatcgatgcc cagatgcgcg ccctgcgagc 43740 ggaacggcac caacggcagg ggtacgagat attactgcga gccgagatag acaagtgcaa 43800 aaagtaagcc cgggaaaccg ggctttttcg ttactggggt ttgcgtttac gccgctggcg 43860 catccggtat ttgaactcgt cccatcccca ctggattaag accagcatta tcgccagcgg 43920 ccaaaagata accgcgaaga accgaccgac tgactcgtcc tctgacgtta tgccggccat 43980 gagcgccata cccagaatcc agaccaccac taacatgatg tcattcagca ttctttaccc 44040 tccacgcgcc gcataacgac tttgaaaatt tcagcgtagt ggtagcgttc ggatgtaccg 44100 ttagcccagt tcaacttaat gattagacca tcaagctgtt cggtgctgtt aacgacatcg 44160 ccgctactta acacgtcgcc cgggcgcagg ttaactgcgg cgacaggggt ttcagttaat 44220 gtcgccagta cacggtcttc cagtttggag aattcatgta cggtcaaagg cccatcggta 44280 tcccacgcct tacctgcgcc cggagacatt tgcatgaaac gccggtgggt ttcttcttcg 44340 ttacggcgca ggagttcata cattccctgt agtccggtac ggtccgggag gatcagctga 44400 atcggcagac ggacgacctg gttttgctgc gcggcccggc gtaacgcgtc aaaactgcgg 44460 tatacctgga tgcccagctg gtacgcgcgg tggacttccg cctttgtgcc ggtgcttacg 44520 acgtccgcgt ttggcatggt tagcagtacg gcgtcgcaac gttccagcat ggccatcgtt 44580 ccgtccaaga aatactggtc gtcgttttgc ttcgcctgat tttcgaagtc ccgggtattg 44640 agatgcggca ccaccgggaa cagtccgaga tggccaagcg tatctaccag gtgaacggcg 44700 gtaagttcgg cgatgctgat attatgggca gtatcgacta acgcgccgca ggcgttggtg 44760 taagggcggt acggcccggc aatgtagatc agtttcattg gctttcccca ttaattcgtt 44820 tcgaacttaa ctttgtccat gtacttgtcg cggaaaggtc cattgcgcac agttcgtctt 44880 cgttgtttaa aaacagaacc cagttacgtt ccgccatttc agcagatatt tcggcgatga 44940 attcgtcggt gatctttaat cgtccggata tatcccgtag ggtattccgg gagaatttat 45000 atcggtttat ctcgcgccct ttctctgtgc cgtatgcatc cgcgttggaa attatcagat 45060 tggcaacgtg acgcgcgccc ctgaccgcca tcatttcata cctttgaagt ttttaggatg 45120 gccgatgtta ctctgaacat cgatagtaat ttcatccatg aagcagggca cgcggacccg 45180 caccagtgtt tttgcgttta ccatgtccac caggcaagtc gtttgcccgg ccactgctgc 45240 gttaacccgt tcatgccctt tcgccttcgc taactcgcta tacgccgcaa ccgtatcggc 45300 gaccatattg gccatgaagt cccactgggc ctcgtttatc ttccgctgga tgtcgtgggg 45360 gatgaccgct ttattcgctt tgaacatatt atttcctccc catggggcga tgtgagccga 45420 tccctttctg gtggccgatg tggatcttgc cgcacagttt gcagtggtag gcatccatcg 45480 gcccgctgta cccgtacgtc cgcttgatat accggatgcc tgccagagcg gccgggatgt 45540 ccggataacg ttgcttcccc tcgcatgact tccggcgcag tctgcgctta ctggccatcg 45600 ttacaggctc cagttaggca ggatgcccat ggcggccagg atggctgcga tgacgaacag 45660 cgcagacagc aggcagcaga taaatccggt gcggcggttc gtcttgtcgc cctccagcgg 45720 caacgactcg atatactctt ccgccttctt acggcctgcc tcccagcgcc agtatgcccg 45780 gcatttcgcc ccggtaccgt tagttgggtc gctgtacggg ttgctttttt cggtggcgcc 45840 ctgcaggccc gccagcacac cttctgcttc ttccagagta cgggccggga tgaattcatg 45900 cgcgccgggt accggtactt cgtagccttt ctcgctttct ttgatcatgg gttaaccctc 45960 gtagttcatg ttaaaggtga tgcgtattac tgacttaata cccaggtgat cggtaatcgc 46020 caggtaattt ggtggctcgc tcatcatggc gaattctttt accgccatat acccgggact 46080 taacggtctc cccctggctt tcatcccggt ttcataggcg gagacgaacg ctttggcgct 46140 gacgacctta cggtccagca caaatcccca ttccatgagc aaggggtaac gcggtggtgc 46200 agttttggcc gttggcttat cagcgaatct acggctgctg cgataaatgc cctgcgggat 46260 ggggtacacc cgacaaaccc cgtgatagcg ccccagttct tccagcccat agaaggtgtt 46320 gcagcggata tcgtattcgc gttcgccgtc cattaatgcg gcaactgcgg ctttcagttc 46380 gtagtaatac tggaaccact ggtggtggcg gttgaccacg cccgaaatga tctgctggtc 46440 aatccggtga acaatctggc tcataatgaa aaactcccgt cgttgccttc gggagtaata 46500 ttagttgcac acgaatcgta tgtcaaacag ttttttaagt tattcaggtt caggttttag 46560 ccgcgggaat ctttccagcc agccgtgatc gataatcacc atatacgcct ggcggtaggc 46620 atcccgtatg gcagtgtgtt gcgctaacgg gcagcgcgct tccgcctgtg cgtcagcgag 46680 ttcccacagg ccgccttctc ccggacggag acggtcccac cgcttcatta gcgtgcgggt 46740 atcgttctca tcccgaaagt cccacggacc ttttccctct ccgccaaaca gcccgttttc 46800 cagttggata atatccacgc gtggtgcatg cccccaaacc tgcgggcgga attcttccca 46860 tgcttgatag aggcccatgt aacccagttc atcctgaccc ggggagcaca tgtattcttt 46920 aagcgcctgg tgtacccagc tcatgaaggt gatacgagcg tcatcgatcg aaaccggttc 46980 agcatcttcc ttcgcgaaaa acgcttccat tgcggcttcc gggttttgca tcgcctgact 47040 gacccaccac ttaaccgttt cagggtcaat gtcgccccgg cggcgacgac cggcaccctt 47100 ggctaacgta acgctgaact cgcggaacca gccttcgtcc gcgtggaaca tgacgcacgc 47160 gaatgacaga aggtagccgt cggtcttgca tgacaggttt tccacgtcga atacgaggtg 47220 gattttgccg atgtgttctg gttttgctct cataggtgtt cctcttcttt ggtccattct 47280 ccgctgccgt cggcgcgggt cactttaata atttcgtctt tttccacgtg catcaccggc 47340 agcggtggaa atgctacggt accgtcggtg tggcataccc gcacttccac ccgccagggc 47400 ttccagaaaa cgggtatcca gtcgcaatgc tcaatcacga tgccggagta ttcccggcca 47460 ttgcatttat cccggaagcg gaccatgtcc ccgtagagcg ggtaatcagg gtccggcggg 47520 agggcggcat atttatccgc aattgatctg caaacgtcat acattgacat attaatcccc 47580 cataaaaggt tcgcagctcg ccgcgcaacc ttcgtaatct tccggagcgt cttcacgaac 47640 cggcactgtc aggtcgaaac tggcgatcag ctgctgcgta tttcggtatc cccggaagaa 47700 gacccgtggg tcgtctacct ttaccccttt gaccatgttg tcgccaacgc ggccatagcg 47760 ttcttccatc tcccgcgtcc actcgaagaa gtccagcacg tccagcttgt cagtcgggaa 47820 ccagtcgatc agcgggtaca cgcggacctg gcccgtctga cggctaaccg tggtcttctt 47880 acgctgcagt tcgtccgtac gaatgccgat cgccgtctgg taggtgccgc gcttccagcc 47940 gatggaccgc atgtacgagt ggatcacgtt ctccttcaat tcccgggtgc aatggatgta 48000 gtttttgttc gggatgccgt actttttgag catctcttcg aacaccctgc cttcccggtc 48060 cgccgtctcg tacgagatga cccgatgggt acagccgcgc tttttgccgt ggtgaacaac 48120 cgcttccagc cataccgtgt tgaagccgaa gtgctggtcg cagtctcgta cgaagtccag 48180 cgtttccgga ttctcacggc cggtattggc gaagcacacg ataatctcgt acttatcggc 48240 gtactctttc aggatccggt aggtcatgta agcggaggtg cgccccccgc tgaacagcac 48300 cagtaagcgc ggctttgcca ttagaaatcc ccgtctaact cgcccaggtc atcggcacgg 48360 ccatacagct cttcgaacag gatcatcgct gcggcgtaca ccagcgtccc gcgaagttcg 48420 ttgatccggg cctgtttagt cggcagcgtg cgggcctcaa tggttttctt gataacctgc 48480 tgcgccaggc cggcgtcgct gtccagcata tgcgccatgg tcagaatcgg ctgttcgata 48540 aacggcaggt cattggcgtg acgctcacgg cctttaccgt acgccgcctg ttccagcgcg 48600 ccgaggaagg tgcgcagcag cggcaggtag tcatcacggt ctttctcgtt tttgaaccgg 48660 aacaaggtcg accggatgcc ggaatcatcg gcgaccatag tcaggtccag gtcgtcatta 48720 gtatccgtgg ttgatgggcg taactccgga gcgaactttt catactctat gccctggcaa 48780 tcctctgctg ccttatcgta cgcagaagcc aggccactcc atttcagttc ttcaaccgca 48840 cctactggca gtgtcacgtg aggccatttt gcaccagcct taatcttgat gcgttgttcc 48900 ggaaacaggt ccggagcggc ttcgtttttg atagtcacgg tatttttagc atgagtgttt 48960 ctacccgcat cggcggactg gcgggcttcc ggttccactg gccggggggc gacgagcgta 49020 tcgatcgctg acaggatgct ttcgtctgac gattcgaaat caagttttaa cgtcgctgca 49080 atcgtttcca aggttgtttg gtgttcaaac gcctgcgcat tcacagcgcc taccatggcc 49140 agcatttcgt cccagctgcg gcctgtaaca cccagcgcgt tcgccagctg gtcacgcatt 49200 tgcgaatcaa tgctgaccgg ttcgtcaatg gacgggttac gcagcgaaag gagtttatgc 49260 ccgttgagat gcgcgaacat gagatagttc atcgcgtcga tcaacttacc cttggccagc 49320 gaatcgcgaa tgcaggtacg gcattcatgc tcggtcagtt ctttccatgg ttcagcggtc 49380 gcccagcctt tgcgcttatc cgcgccgtag taaagacgac caagcatctc atcgaagacg 49440 cctttaactg aggtcaggaa cgcttcattc aataaattgc tatggaaggg cggccagcgg 49500 agttcggttc tcgggtgaac gattctgttt ttggccggca tttctttatt ctctgacatg 49560 gtatatctcc gggttgtttt gttgttcgat tagaatacta gctgcacacg ttttgtgtgt 49620 caaacgtttt ctagaaaatc tacagttccc accataaagt ttcggatgaa ctgggcgccg 49680 acttgaggga cgattgcatt gccgtatccg cgcagtcgca ccactcgggc gggtacccca 49740 ttagccaacg ggaaaacgcc ggatccaacg ggcctgaact tcccatcccg gcatagcagc 49800 cagtcagcat ttgaccacgg gccgtgatcc tgatcgggaa gtcgggggca ggcgtacact 49860 tctccatgcc cttccggtag ctccccgata gctgccccct cgatgccggc gagtccggta 49920 ctgtcagcgg tgtcgggtag ctggcgagac gaaccgcgcc gcccagggtc gtcgaccgat 49980 ccggatggcc cgctgcgccc gcctccccgc gtacctgatt gttgtcgatc gtcgtcaccg 50040 ttggccaggt cgccagctgc gccgccacgt ccagccggtc gacggatagt ttgccattcc 50100 ttatccgccc acccgcgtag ccgcctttcc agtccgtcgc tgacgaggtc ggccaggtcg 50160 atagcgccaa agaaaaggcg atctctttta tgcggggcgc cgacgctgca cgctggcaat 50220 actgccgacc cgcaggcgta accttcttct tccagctcaa cgaatagagc atcgagccac 50280 aattctttaa ttgctgcgct aacctgttcg ccaaaaataa ctggaggtcg cagctctgcg 50340 atgaggtcga gaaaggccgg agccaggtga cgggagtcgt cccgcccgcc tcgttttcca 50400 gccacactaa aaggctggca cggcggactt cccgtacaca ctggcgcata cgccggccat 50460 ccggcgagtt taagggccag cggccatccc ccgataccgg cgaagaagtg ccactgacgg 50520 aaaccccgga ggtcttccgg ggcgacttcg gtgattgatc gttcatcgac aattccatct 50580 ggcaggtggc cgcgcctgat tagttcacga agccacgctg cggttttagc gtcccactcg 50640 ttgtagtagt ggaacggttt agagccgttt atgtatgcca ttctgcgcct tcttctcttc 50700 gcgtcttttg accgcacaat cggcatggat cgtagtccac gttccggacg cagacctttc 50760 aagatacccg gcgccggccg gcactggctt tttgcagtag caacacatag ccacgtattt 50820 atttctggcc atctttgacc ctcgcgaaac aggcatacgg gccatcgaat tccgtcggcg 50880 ccgtatacag gagaaaccag ccggacccgt taagcgacgt cgggcgcggc atccaggtac 50940 gcagcacaga ggcgcgcatc tcgtccgtct tcgcgttgtc gtacgccacc cgcagcggca 51000 cttccagcgc tcgcggatag ccttcgccca ggtagaatcc ctcgcactcc aggttgtatg 51060 catccagcag cgcgtcgaga ttggacccat catagttatt actggcgtgg aagaagacgg 51120 gatggtagta ccaggcgtcc gggtcatacc cgtccgccag gcttacctgc tcgccaatta 51180 cgccatcgtt atacacgttt ggctttggca ttcttccctt cctcttcggc aactgaccag 51240 acgacctcgg tgaacgggtc agggttgatc gtcttcccga ccttattctg gtcgaggtac 51300 cagtcgtcgc cgcaccacag tttgacgccg tgggcatccc ggcggacttc aacgtcgaac 51360 gttttcactt cggtgatctt gccgttacgg gttacagttt tggttaattt catggtcttg 51420 gcctcacgtt tatgaacacg aacctgtttc atgggtcatt ccccgaggta attcatggcg 51480 ccgcaatccc ggcatacaac ttcacgcggt ttcccttccc acgtccattc cgtcacatcg 51540 cattgatagt gactacagct atcctgaatg cgctgcgttt cctgccgttg cgcttcgtat 51600 ttagcgtcct gctcggcgcg gcgttcatcc cgtaaacgct gcttgcgttg ttttgatgat 51660 tcgaatgtca ttgctatacc tcgtcccact gggcgatcca cttctcgcgg acgtcctgca 51720 tgatgttggc catgggcagt ccgatgtcca tgagcgcttc ccgggagatg tactccgggg 51780 catgtttttc ttcgtcttcc ggatcgaaga tgactatcgc ggcgccgaag cccgcggacg 51840 ttgcacctgc ggcgcccgtc ttcgctttga accataccgg cggttcgaaa ccgatacgcc 51900 ctttgatgaa tatggtgcgc gtggcgatgg tatctggcca ccatgtttca gcggtagccg 51960 ctttgatcac ccagaccgta cccgcgcctt tcttccgttc ctcttccgcc ttggccatga 52020 tgttgaccat gccggtcagc ggcacttcca cagcacggtt acggctgtat ggcgggttgc 52080 cgaaacccca tacccgccga acgtggtcgg cgacatcgta cacttccgcc tcggcctcca 52140 gttccgcctg tatccttttc agccggcccg cccagtcctg gcgcagcgcg ttgtcctcgg 52200 cggtgtaata gcgcgtgcat ttggcgttct ggccatcggt gaacaggtcg agcaccagcg 52260 ggccgaacag cttgtccagc gcgaagaaca gccagtcggg tgttcgccac tggtcgccta 52320 tctctttcag gtcatgcgct tcccgggctt tcagcgcgat gaggttgtca acgtattcac 52380 tcacaaatta gcctccatgt atggacttgg tcgccctggg tgatgagatt cacaatgata 52440 aagccgcctt ctttttccat tcgcgcttta tccgcgaatg ccggaattgc ggcaaggaag 52500 tctttccatg gcagggggtt aaacgcgcca atggctaccg agatttccag gtttttattc 52560 ccaccggcct tgtgggaaac gcagcaaagg ctggttccgg ttttatcccg cagccaacgg 52620 tctacgctcc ggaggaattt cccgtctccg gcggttaaaa tgtcgcactg gacaacgata 52680 tttgtcacgt cactcatggc cttttctccg ctaaaaattc gcgtaatacc ttttccatgg 52740 ccaattcgtt tgccgcagcg ccaggccatt taccgagaag ccgcgcatta ttcggtacgg 52800 tctgcatttc cacaagacag actttgttac ccaactcatt gcgagaatgg ttgatactca 52860 ggctgtaaat gctgacgtcg tccgggccat cccataggtc ttttcggata ttaagatatg 52920 cctgaatatt acctgcatcc gggatcgcac ctgcgctcat aatatctacg cacatttcct 52980 ggatgacctt ttggtcgtta attacgtttt tcatttccgt ttttccttct gtcgtgacac 53040 gaactggact ggggtgacga cctcaccgaa attcgggtaa cggctgcgca ccagctcaag 53100 ggtcagcggg ttgatctccg cacgcggcgt cttcacgtcg tacgcgcggt ccgggatgtc 53160 gatgcggcgc atgtacgtcg gtcgcatccc gacgcgtacg gcgtagttat acgcttcctt 53220 cgggccgttc gcccagacca cgaagccgac cccgcggcgc tgcagataat atgcctgcgc 53280 cgtattggag tcatcgcgag gcagattttg tggtatcgcg ggaaaacggg cgctacttcc 53340 tttcacggtt cctgtatacc aattggtcga agcatggcgt tcttccgaac actccggcgg 53400 gtacgggtca ttgatatccc acgtctttcc gcaccaggaa cagaacacct ggtccgattg 53460 ctggatagcg tttttgtggc cgttagtttc catcggtgtc ctccatcatc caggacggcc 53520 atacgccatc gcggatcatc tggcgctggg ccttccagtc ggcctgcgcg agttctttaa 53580 ctcgggtccg gatgacagcg tcgggcataa acgccgtcat tactttcgtc aggaaaactt 53640 tgttgtaggg gtcctccacg cggcagttta acgcccgggc gcaggactgg atcgccgcct 53700 tatcattgcc gtgttctttc atgcacagca tgagcgtaac gatcatgtct atcgcctcgg 53760 cgatatcccg gcacgctttc ttttctggcc cgtggacctc aatggaaata ctggtcgccg 53820 ggaataacag gtggtctttg tacgggcgca gccagtccgc tttcgcccgg tcttctgcgc 53880 tggtggtcat acttcgatgt cctcttcccg gatcagctgc agggcgttgc cgttcactgc 53940 ccacggttgc cacacgtcca ccaccagcgc cgcacggaat gaccggttga agcagttctc 54000 gatcatcgcc cagttatcgt ccggacggtc tgacgcaatg ccattgcgtt cccagtgcca 54060 ctggcgaggc gcctgggcca gctcgcggag gggcgggcgg gggtgtgagt agggattgca 54120 caggccggaa cgcagcaggc cacgctggag ccatgagcgc tgccaccaga ggtcacagcg 54180 ggtcgacccg acggcgtatt cctcttccag catgccgcac atgatcagcg cgcacacagt 54240 atcgcgtggc gccggcgcac cgatgaggtc gaaatcctcc agcctcttcg ccaggcggtc 54300 ggcggaccct tcgtcctgcc cgttgccgtc ggtacggtca tgcagaatta catcgaggat 54360 gatggccgga aaaacgactt gtttgccgtt gcgggtaaag cgggggtccg gctcattgaa 54420 gagggcgtga tacagccgcc cgaaccactc cgacaggtca ggcacgaagt cggcgatatc 54480 cggccagctg cgttcctctg tgttgtggat gcgcacggac gtctcttcct ctatcgggtc 54540 gtactcgacg cggacgatgc agcgcgggcc gtgcgggagg ggaaaaatgt agatggtctg 54600 tttgccgatt cgattctggt caaagcggcc aaacgacatt agatgcttct tcatgggatg 54660 ttcctttttg tggactccca agaaatgtag ctgaacacga ttcgtgtgtc aaacgctttc 54720 tgcaggcaaa aaagaagccc ggacaaagcg tgccgggctt taatgtcagt ggaacaccga 54780 gcatgaagat ttcatcccat gtcccgatca ctatacgtca ggattgcgat aaatcaaatc 54840 ccagtaggtg aatgtttcca ggtcgacttc cgtccagtcc gggtcgtcca ggtacgacag 54900 gcaggtgccg gcatcctcgg cgcagacctg cccggcggcc gcattatgca gcaggcggac 54960 ttcccggaaa tagatgaacc actcgcggca tggcgtatag gactcgggct gacgggtctt 55020 gatgatctgg cccgtctttt tgtcctgcca gtacgccgtc cgtttcttcg ccaggtagcc 55080 catatcagcc caccctcatg acgcgggatc ccatgcggcc gtaaatcggg tcgcgcagca 55140 cccagcggat agccagctta taccccaact ggtaccccag gcgccgcacg tagcccaggt 55200 ccgcaggccg cttgccgctc acgaagaagg actcgccgac agccatagcg ccaagcaggc 55260 gtttatgctc ggcgatatgg gggttcggtt tagcgtgttt acggcctgcc atgtcacacc 55320 tcgtcgtcgt cttccagctg cgcgtcgacc tcaaccgtga tgtccatctt atcgcggaag 55380 acgtcaatga cgtcctgcag cgacagcacc gtctggaaca ggttggccat gtaggtcagg 55440 aacgtaccgc tgtcattgtt gtagcgctcc agcgtggctt cgtagttggc gtcaacatcc 55500 gcctcgccga tgtggatccc ggagatgatc gccttgtcgg taaggcggaa gaacacgttg 55560 cccacgcccg ggcgcatctc gccttcgtcg attcgcatgt tcagcgcccg aaccgtgtaa 55620 tgccgcgcca ggtagtcgag gaccacttcg tccttgtgga tgtcaatgtc cttgaacttc 55680 acgtcatcgc catcgtcgtg cttgatgtgg atgaagtcct cgccggtgac accctcgatg 55740 tcgccgcgta cgaccttctc cattgactga cgcagcacga agtcattgat cagcaggtgt 55800 tccactggcc aggtaccgaa cgcggcacgc agtagggagt taatctcttc ggcggtcctg 55860 gcgctggtgg tgaacacgta gacgtacggg acggcgatga tcacgttgta gcgggtcggg 55920 cggataggcg cggttttcag catttcggct tcaacatcgt ctttcagctg cgcccagtct 55980 ttccgggtcg gctcccagcc ttcaatctct ttctcgcgcc aggtgtccat acgcttcgtc 56040 acttcgttgc gcacgctgac gccgggcagc acgcgttcac gcttttcggc ctgcagcacg 56100 atggcgttag tacccgggat gcccatggca aacttgccgc ccacgtagtc cgcgtacggc 56160 gcaaagccaa tcgtcttata gccgatcggg tctttcactt catgcttcgc cagcagatcg 56220 ctcacacggc cggcggcgaa ttcatggacc gacatttcgt ccatgttcgg cgtgttcagc 56280 agcgtgcggt ggaaactttt taccgacttc tcgccagcgt ttgcggcgcc aaagagcgcg 56340 ccgagatgca gaatgatgac tttctcaaag cctttaactt tcattggggg tatctccgtt 56400 tgcaaacaga ttcaggaatg gcgcacgcac aagggcggcg gttagatggg ccagcagcac 56460 acggttcgtc tcccgggcgc tacgcaggtc tgccgccatt tcggcatact ctttatcgac 56520 tttgacaaag gcaccttcgt cagcgtcagg gtcgaccatc gtgttgccga ggacttcggt 56580 atacacccgg gtcgcttcat cctcgatgtc ggcgataatg ctgttcagga tggcgatctt 56640 actgcgtacc tggtcgagcc ggtcagcgcg ggtcgtcgcg tacgctttca gcagttcagt 56700 gttcatccgc gtgctctctt ttcgttacgg cggcgctggc gctcatcctt gcgcttctcc 56760 acctgtgcat tccagcggtc gcgttcctct gactccgccc ggttcttgag ccagagttcc 56820 tcccgttcgc caagcgcttt actgaccgca ccgtcaataa cttccgtggc ccggaccagc 56880 tcgtcttccg tcatttcagc ggcagagcac ttcccgatct ccgtctgcag caaacggaca 56940 acggcagaga tgccgatcgc gtcgatggcg atacgggcct tttgcgcata cagcagtctt 57000 tggttaaccg gcatcatttc acccccgttg tcaggacgac atagaggacc gccacgcagg 57060 cgaccagctc gatcagcacc atgaacagga tggacgccag cagcagtttc gcaaatgacg 57120 gcaggtatgg agtaaggcgt atgcgagcat gaccgtccag ctctttgtgc ttcattggtc 57180 ggcggttacg tttggtccag cggcgtatcc agttttcgcc gcggcggtgt acgaggctat 57240 cattcatcac ggttccctcg catggcatcg cgcaggtctt tcggcgggta gattttattg 57300 acgccatcac cttcacgcag gaaacggatt aacatggcca gggtctgcac gatctcttct 57360 tcgacatgga cccaggtatc acggcgctcc gcgtaatgca ctgctgcctt gatcacctcg 57420 ccggcctctt ccgagaattt cagcatggtg taattcggct gcgggtattt ttcgatagcc 57480 cgggccgatt cggctcgtgc ctggtcgacg aggatatcga aataatcggc cttcgcttcc 57540 gcctgcgaat tcatctgcag gtaaaagatg gccagcgtcg tgaggaattc cgggctggcg 57600 aaagtgatgt ccccacggcg taccgcatcg cgataccggg cgacgctttc cgggttgact 57660 tctctgaact cattttcatt tgacatgggg tttccttctt agtgtttttc gccagcaatc 57720 tccgccagta cggcagcgac ttccggcgtt ggcatgtggg tgttagccca gtacagcagc 57780 ccgatgatgt agtggatcat ctgaccgacc tctgccgcgc cgcgggcttt tccgcctttg 57840 gctttcgcat aatcgccttc gctgaacagc actttgccgg taccgcggta gccaacaatg 57900 gccgaaccgg tatgcgtgac gtaaatggcc acggcgtatt tgtcttccag ggatcgaaac 57960 gccgggccag cgtcgagtcg tttgcgcggc gccgcaacgc ggttcaccgc cagcgcgaca 58020 ttactcggtg tcgggttttc cattgagcgg ctctccgttc agggtgtaga tgacgacgcc 58080 cggcacgctg acgtcgatcg acagcgatgg cacaaagccg gacatgacgt tctgcggggt 58140 gatggtggcg cgtttcaggc cgttctcgta catgatgttc gcgatgcctg ccatgacgga 58200 cttctccacg atgttctggt tcgtctcttc gcgcatggtc agcagctgtt tcaactcttc 58260 gacttcattt ggaatgtcaa aggtatgctg taacatccgg ataagcgtaa tggcatcatc 58320 acgggtgatc ggggtcagta gctgggcata agcagggtca atatggtcga tcatgatctc 58380 gccatcctgc tgtcctggct tacggtaggt atgcaggact cgcgctaact cagggtagcc 58440 gggcataatt tccgacgttt tcctttggtc atcatatgac atagggtgtc tccgggtgaa 58500 aagggtggta cggcaaaaaa gaggtgccgc gtcctacagg attaaacttc gtcgtcttcc 58560 ggtgtgccgg cgccgtcatc aacgcgcttg atcgccacct ggataaacgc acggcccgac 58620 gggtacatga ccagcgccgt ttccagtgag aactgactat tgcaggcccg tttggcgtta 58680 cgcagggaag acgacacgcc gttacgcatt ttgtagcgca gcgccgtggc ttcggtctgc 58740 aggtctgcca gcgccttgct gctgtccagc tcctgcgcat aaacgtagac ctcgcccggc 58800 ttgaggccga tcaggttgcc agtgatactg ttagcccgga tacctgacgg cagttccacg 58860 tccgtctcca tggtcatcat ggccggcgtc aggtcatcca ggataatcgc gtcgttcatc 58920 ggtattctcc gtcgttaaat ttgcgtatct gtcacgctga aagatagttg catacgttcc 58980 gtgtgtcaat cgttttcact gcagcttttt caagtaagaa atttcagccg gctaactttt 59040 tgaagtaaga cccgaaccgc tatggcgccg gccatggtta ttacggg 59087 <210> 2 <211> 585 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15/09/U2874_KPN_BP ORF49 <400> 2 atgtcgctat cggatgacga gtaccagaag gccgcggcga agatcggaat cagtgtacct 60 gcgctgcggg cattcgcgga agtggaaagc aatggcagcg gctttatcga tggcaaacgg 120 ccaaaagttc agtatgagcc gcatgtgatg tatcagcggc tgaaagagaa cctcggggtt 180 agcgttgcta atggtgcgct gcggaaatgg cctgacctgg tggctaccaa acccggcagc 240 tatcagtcgc tgaacaagga agatcaggac atggaccggg cggccaaaga gattgaccgc 300 acaagcgcac tggaggccgc cagctggggg gcgtttcaga ttatgggcta ccactggaag 360 acttgcggat acccggtgct gcaggcattc gttaacgcgc aatactccga ggctgggcag 420 ctggacacac tggtccggtt cctgcgtgca tcgccggcca tcgtatctgc ggtcaaaagc 480 aagaactggt cgaaggcggc gcagctgtac aatggcccgg cgtataagaa aaacgcgtac 540 gacgataaac tggcgaaggc atataaaaaa tacgggggtg tgtga 585 <110> Industry-Academic Cooperation Foundation, Yonsei University <120> LYTIC BACTERIOPHAGE SPECIFIC FOR KLEBSIELLA GENUS RESISTANT TO          ANTIBIOTICS <130> DPB172743 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 59087 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15 / 09 / U2874_KPN_BP <400> 1 atggccaccg tggcgccgca ggaattttac ctcaaggatt gccgggcatg gccaccggtc 60 aggcccatgg cgccgacctg gctggcgcgg cccgccgccg ggtttcagcc tgccagcttt 120 ttcaagtaag cgcgcaccgc taaaaatttt cagcccgcta ggtttgccaa gtaaggaagc 180 ccaaaatttt tatagaaaat ccggatttcg gcgtccccat ggatcccgaa aaaggtgcga 240 tttctgtaaa ccattgattt tattggttcc gcggggatgg cgccgatggg gcggaaaggc 300 cagcaagcca ggcgtggcgc gggttgcatg ggtatagatc cccgttgggt gacggcgtgg 360 cggcgcgccc tggggtgacg cggaaagcaa aaatgaaata aatctgcatc gaggggttgc 420 acacggaatg agtgcaagtt atgtttatcg aacccggcgg ggatacgcga acaacgaaac 480 aacataaacg aggtaaacga aatgaaaaag attaaacgtc tggcactgtc ctggtctgtc 540 tcccgcggtc gtgacactta cggctacaac atttgccgcc ttgatgacac atcaaccgga 600 gaccgcttta aatgcatggg cggcgggtat gacatggtag ggacggtgtt cggtgactgg 660 ctggccgcaa actatcagcc tgaattgttg gcgctgaaag atcgcgctgg ggccgtgtgg 720 gaagaggcgg gcggccgtaa atcggcggac cgcgcggacc gcctatacgg catggtatac 780 cgggaaaaag atagcgtagt tatccttgat ggcgcttgcg ggcttgattg catgatccgc 840 attgctgagg ctatcgggct ggaagtggag cgcgattata tcgctaaagg ccgccgccgg 900 ggtgagactg tgggctggta tgtaagcgag gccgaataat gataacaata atgtttatcg 960 gttatttcat tatcggcgtt tatatcgggg cggacgtccg ccgcgtttta aagcgttgcc 1020 gtattgagcg ccgcccgtgt tttggtcgca tgactattta tttgcgtgaa cgtaagaccg 1080 gacggttgat cggctgttct aataacattt tcactttaat tttgcagggg tcttgatcat 1140 gagaattaaa atagaatcgc ataaatatgc gccggaatta aaccgcgttt atttaaccgg 1200 aaaaaattca tcgagcgcgg cggtactccg cgccccgtcg gtaacgtccg taaaagatgc 1260 ccgcgcggcg ttattcccta aagcgcttcc attccgccgg gttgtaaccg tggaatcata 1320 ttatgatgat cctcgttttt acgggcttgg ccgccgctat tccggaaccg tggattcata 1380 cgaacatctt aaaaacgtga tcgctaacat taaagcccgt aacactgggg ggccgctgtt 1440 agatgggtcg attctcccgc cagtgaaagt gcgtattgtc tcaataaaag ctatgggggc 1500 ttaattatgt ttacctcaaa cgttgaaaac cgtctggcat tgccagccgt cattaccgcg 1560 cccggcgact acatcacccg gtccggatgc cgcgtcacaa tcatcggggt atcgcctgtt 1620 aatagccatt ataccttccc ttgcaagggg tcagtatggg ttaaattccg cggggcgatg 1680 cggccgcgtg gatataacgt ctggatgcgg tccggtcatt tacacgccgt gggcgatcat 1740 ccgctggata tcgtcgggcc gtgggaggac ttgaaaccat gaatagtgac gcaaaaaagg 1800 ccgtcgtaaa gttctccgcg tgcggcctta tcgctggctt taccgtgatc gccattatcg 1860 cgggcgacgg gggcggcctg ttccgcccga tactttacac cgtggctgga ggggtatgct 1920 gtgggctgat atggcccaca caggaccagg gcgacgccct gctggactgg atcaaagaag 1980 ggcggcgata agccgccttt cttattggcg ctgatacccg aaccgcgaaa accggggtga 2040 cgcggacagc aaaaatgaaa taaatccggc taaggggttg cactcgttcc gtgtgcatat 2100 tatgtttatc ggacccggcg gggatacgca aacaacaata aacgaggttc aaaatgacat 2160 acgacgaaat caccgcaaaa attaacgctt tcaacctgaa agatgggatc acgattcgtt 2220 atacctccga cacggacgga tcaaccctgg ttgaactccg cgacgatagc ggcgctttga 2280 tctggtgtgc ctggtccttt gaggctgatt ttgctttctg cctggatcgc gagctggacc 2340 gctacggcgt gaacaaatca gcggaggcgt attgcgtcgc tgataaccgc cgcccgtccc 2400 acgtaaaccg cgcggactac gcaacggacg ccgaatacag cgccgcgaag gtggcgtttt 2460 atgcgcatat actccgatcc ctgtggtccg tacgcgggaa cagcatttac cgtcgccagg 2520 taaagaaaac cattaaatca ctgcgagact ggaaagcggt cgcacgcaag gacgcggacg 2580 ccgccggggt ggcggcggta ttcggtaacg ccctcatggt taaacccgtc aaaatcacta 2640 cggcgggcgg aatgaccctt atcgcctcgc aatccgatat aaagatctac ccggctttaa 2700 tgcgcctaac ggcattgtgg gatatgcgcc acggcctaac ccgtgacacg cattacaacc 2760 attctctgcc gttccactgc atcgcgggga ttgaatatgc gggctaacga tattcgccgg 2820 gcgcaagccc gttacaccat ggaaaaatgg cacgggaatt tagtcgccaa aggctttaaa 2880 gcggctggcg atctgctgta tagccgaaat gatgccgatc taacgtggga tgacaaggcc 2940 cgcgcctgga cggtgactat ctggaccacc gaggggcggg accgtctcaa agtgctaact 3000 attcgcaaaa atccggtttt accggcgtta cttaaatctt ttttctaggg gtatctatgt 3060 tcgcattccg tgatgttctg gaagtcgttt taccggcggt aatgttcgcc gtggcgcttg 3120 tcgtcatttc cagtgattac cgtcgtaaac tccgcgccag cggtcgtaaa ttcaaaaagt 3180 aagaaggggg gaattattat ggcttcggta tggtttttag tggtgacact gtgcaccgtt 3240 aaccctggcg cgctggcgtc ggattgtgat gactatgtga tcgacgggga tttgtcgtat 3300 agcgattgca tcaagtccat cgcacagttc ccggagaagg ctgcattgtt cgcggtcagc 3360 tgtaagcgcg gggaaccgct ggacggcgta gggggtgaga tgtgagtaac tttaaaacgg 3420 atgtaaaagg gtcagtagtc ctactgtaca aggacgataa cctacaaaag ccggtcgcta 3480 ctgtgaacag cgcggatgac gtggaggata tgcgcgggca aatcagagac gcggttatgg 3540 cggcctatca tatcggcgtt atggagggtt tcaatgaggc taaaagtgaa ccgctgaggg 3600 atgacccgag agttatcaag gcgctacaac gcgccacaaa agccgggcgg gaacagcacg 3660 ccgcgcaact ccgcgcgcta ctgaatgaag gtcttaacta gggggaagaa aaatgaaaaa 3720 acgtctgacc gttctgattt gtaatgatat gcgcgacccg tacgatccga ttgtggtaac 3780 ggtgagcggg gcgacgcctg aagaagtccg cgccagtgcg ataatcgcgc atgctgaggc 3840 ggaaatggcc gactttgacg gcgaccctat gacggcggcg gatctgtggg cggtatcgcg 3900 ggcttacatc ttcgcggcta tccccgggac cgtggatttt tactatgtcg ggatgccatc 3960 ggacacggtc gacaattacg atcacgtgat gggtgagatc ctgcatgtga tgggtgagag 4020 cctggacacg tcgcccctat gcaacatggg cgattaaccg cccgccgtat tcccgcccca 4080 taaggcccgc catttgagcg ggtcttttta cgtctgcctt atacccgaac ctacgtatcg 4140 cagcctatcg ccctggccgc tggcatagcc cccggagtga ccagtggatg aaaagaagtt 4200 gcactcaccc cgtttcataa aatacccctt tacgccgtcc taacagcctt tttgaaatca 4260 gattaattgc acgcggtgca ggtgcatccc tgcccggtgg cgggcgcgtt atatcgtgct 4320 gtgggctttc tgtattgcac acggggcgtg tgttataggc gctgcccttg tgtgaccgta 4380 tcaatgcacc tgatgcatgt tcaatgaggc cgcttatcgt agtgatatgg cctgtttttg 4440 tgtcggggtg gtggtgtgac cgtgtgacct ggtgacggta tgccaattct gccgccgcta 4500 cggggggtag acggggcgat cgtgggggta tgtagtaggg gtataccatg atcggggttg 4560 cggctgtctc cgtggcgctg gcgaaggaat ccggatcgaa ttcaaaaagg tacttcccgg 4620 gggtcctggc gtgccggggg tgcgcagagc cgcggtggaa gaaaatgcgg cgaaaccccc 4680 atagccccac ttcggaaatt cctgatttac aggggttttt tcgagttttg cccataggga 4740 agacgtgatt ttgcgttcca ggggtggtgc cctaaattcc gttttagccc cgcaaccgat 4800 tgattgcatt acatttttgg gcggtgctct tacaggatca ggtgtcgtca cggaaggtgg 4860 tttattacaa attacaagtt tactacaaga cgaacaactt gtaataaacc ggtaagctgc 4920 tgttatttat atcttttcct caatatttat tacaagttac aagaaaacaa ggaaatccat 4980 ataagattaa aagtaaaacg taatcggtat gcatattatg tatatgtata agtaacctca 5040 acttgtaata aataataatc gcgaaaaatg atttgcattc aaacacttgc aaattattac 5100 aagtttgccg ccccccgaaa actggtcaaa aacggccatt tttggggaca aaaaacgcga 5160 tttttcgaca aaaaagaaag gggccgaagc ccctttttag cgatttttct tgctcacact 5220 tcgtcatcgt cttcatcgtc gaacggattt ttcggtttcc cgattttctt ttcgacttcg 5280 gcattgtgtt ttttgagcgt agtttgcgcc cattttgtat tcagcgtacc gttttcctgg 5340 aacgcattac gcacacgttt tctgacgaac actcttccgc ttttactatt gaaacagagt 5400 accccagctt gagtaaaacc gagttccatg agcaggtttt tcatgcgtga agtcttcggc 5460 atctcgatgc cctcggcttc cataaatgcg tcgttcaatg atggtgaaaa gataatgtct 5520 ttgcacacgc ccagtgtcac gccgcccttg atcatgtccg ctataaattc gcctgcgccg 5580 tcgttcgctg catcgcgcat ttcgcggaaa gcattagtat ccaacggggc atggccttta 5640 tggttaaacc cctccgagat ctcccattcc atgaaccact ttttgatggc cgcgctgtga 5700 ttttcgatag cccgataaac gttagagaag aacttctcgc gttccttagc cgagccgtaa 5760 acgcggtcca tgtccatgtg gttttcagcc tgcgtggaga cgaccaggta gcggcgctgg 5820 ttctcatcca gcggaagcgc gttgatgtgg ttggtgaaca tcaatttcga actggtattc 5880 accacgtcac gcggctttac gcctttccct tcaacctgga agcggtcgtt cgagataaat 5940 tccttctgtt tgtcgaccgc gctgtaccga tcacccttgt catacacctc ttccacgatt 6000 ttcagaatgt ggccttccgc ccagtcggtg aaacgaccat tcatgaccga gtttgacacg 6060 tacccgatgt tctgggcgcc gagcatttcc cgcatgagca cgccgatggt cgatttaccc 6120 gaaccgtgag caccgcggat cagaagagag tagttaattc gctttgtcgg gtgctgaacg 6180 acgtgcgcca gccagtccat gacgtaattt cgctctttcg tgtccggaaa caatacgacg 6240 aacaggtctt tgacgatcga gatggccttt ttatccagtt ttgacagctt ttccgctggt 6300 ttagggatac tttcaggcga aaaagtgttt aaacgtagca aaccggcgtc gtcatagaag 6360 aattccggcc ctaaaagtcc ctctttttgg gtccatttcg attcaggcat atccccgtgc 6420 atttcggggt agtacataac atcgtgaata atagggattt ttacgacgtc cgtggcgaac 6480 ttattcggcg ataaaccgcc ttccacgtcg ccgatatcac gcccatggga cgaatcaaac 6540 gcgctttttg acagtaaaat cccggtttta cggctaacaa aggcgtcctg ggcctgggca 6600 aagacgtatt ctttcagcca agtcggggta tccgcacggg aaaagtcgaa actgaggtac 6660 tctttaacgg ctttgttagt cagcgcgctt tcgttcaggc gtttgtaggc tttcttggcc 6720 gcgtcaatag tcggctggcg ctcaatgccg aaaacccgca gcttacggaa gtcgtctgcc 6780 caggctttcc agtccgccat ggtggtgact tcgttgaatg cctcggtgaa ctcggaaacc 6840 tgttcccggg cttccttctc ttcgatttcg tggaccgttt tgatgatggt gccgattgtc 6900 accagcgtct gggcatcatg ggtaaagcct ttttcccact tgtactcgaa ttctgactcg 6960 tcatagttat ccgcctgcat ggaccagtcg cgggcgatct ctttcgcttc atcctgatcg 7020 cggcatgaca cctgcagcgc tgccattacc cggatccagt tttcatagtt ttccgggtca 7080 gggtatttca tgacgatatc gcgcagctcg tcgtaggtgc cgtcccactt ggtgacggtg 7140 gccattgccg cccagtcgtc atcgtccgct tcgccttccg ccgcccgccc gttaatggcc 7200 cgtgcgactt tcatccatcc ctgtttttcg gcataggcgt cgaacgcgtc ggcgatatcg 7260 cgggcgatct ccagcgttat ttccggcagg tccatggcgg ccgcgcagtt caccggggta 7320 tcatcggtga tccaggtgta ttccttgcgc gtatccgggt ggataccgaa ggcgacgaac 7380 tgctggccat cacccaggat ttcgactgca tggcgctgtc cgaagtcatc ttcccaggtg 7440 gcggacttga cctttttgaa cggctcgtcg gtatggcaaa gcaccagttt tttcggttga 7500 cggccaacac gaaccgggcc ggcgccgatt ttcttttcga caacggccat catgtgctta 7560 accccgtctt tgtcgtagac gtcaatgtct accgcggggg tgtgcttggt caggatgccg 7620 atgccagatg acgcgtattt cttcacgaaa ccgttaatct ggccacgggt attctcgatt 7680 ttctgccagt cttcgaacgc aggccgtttt cctgcttttg gcctgggcga gtcaggcgga 7740 atgatgggaa cgacggtgaa gccgttttcc cacagcacta ttccgtattc gttccagtag 7800 ttcattcaag aatttcccct gtatccgggt cgatttttat ccagtccggg ttagtgaacc 7860 aatgtggtcg gatgccagaa gttttagctg cctcacaaat tttgacggcc atctgtccgg 7920 aaacggtgtt gcggatattc cagatcatag tgtcgtaatt tacgccagcc gccttcgcca 7980 gtttggtaag gttgccgtcc gggtctacct ccagggcagc gatacccgcg agataacgcg 8040 gtctcaggga gtggtcttta atagcccacg gtggaaattt catagatgat cctcgcgtgt 8100 gtgtgcgtgt aagtaaaacg gatattagtc tcgcgctgct acaaagtaaa ggggacgata 8160 cccggcgacc cccggccatt tcacaaagat ccccgaaaaa accaatgggt accgaaaaat 8220 atttttgcga aagtgttgac acgggatgcg gcaatggcca tactccaaac cgtcaacacg 8280 acaaacccaa attaaccgaa cgaggattta actatgtcag gtatttttga acagctgctg 8340 gccgaacaac aaaaaaccaa ctccctgctg gaacagctgc tggcgaatgg cggtgtttca 8400 tccgctgcag caggtgaaga cgctggcgcc ggtaagacca ccgccaaagg taaaaccacc 8460 gccaaaggca aatccactgc tgcggcagac aagccgaaac acaccaaaga cgaagtagtc 8520 gctgcggtcg tagcggtgaa agaccgcttt ggcgcaccgg aagccaaaaa gatcaccgct 8580 aaattcggcc tggccaaaat cgccgaagcg aaagaagaac acttcgacgc gatctttgac 8640 ctgtgtgaag ccaaactggc cgaaccggaa gaggatgaag gcaactccga agaagacgac 8700 gtttaatctt cgatcgtgta actcggcccc tgcgggggcc gttttagcag agaggttatt 8760 gtgaataagt tcggaacggc aatagcgatg acgcccggcg gcggagagga agtgcctatg 8820 tgggctgagt tccgcttcga aattggcgac cgtaacccct tattcagagt aacttccccc 8880 gcgcgtggcc agaacggccg gcggattaac ggggaattcc gtttcgtcgt tacccacgtt 8940 gggtccgggt atcgttttac cgatttcagt ttcgacctgt tagcgaaaac ccggtataac 9000 ctgaaacgga ataactacgg aagggccggc gcaatggcgg ttaaaaagac aatcgatgaa 9060 gtaggcgttg aacgaatttt acgcgccata aaaggctacc atgatgagta agtctttcct 9120 ggttcgtgtt atgcaggagt ttgccggcgg cgggcattct atcttcgcgc cgtcagcctc 9180 tgcgatgtgg acggcctgcg gcggaagcct gctggccaac cttttcgaag aggacgagtg 9240 cagctatgaa gcggcggaag gaaccgtcgc ccatggcatc gccgagcagt ggctgaaaac 9300 ggacatccga ccgacgcatc ttatcggaac cacgcaggtc atcgaggaaa aaggcgttcg 9360 gcatgagatt gtcgtcaccc actccatgat cgactacgtt caggattatg ttgactggtg 9420 tcggttcgaa gaaggcatga tgctgacgga aatccgggtc tggttcaccg acctgatgcc 9480 gccagccaac gctgacgagc tggaggaaga cccggacgcc gaagtagtgc cgtttctccc 9540 gcagggcggt accgcggata acatcatcat tcgtgaccgg gtgctgattg tcaccgacct 9600 gaaatacggc accggcgtcc aggttttcgc ggaaggcaac ccccaggcgt tgctctatgc 9660 atacggggcg taccgcgcat tcagcgacga gtacgagttt gaccgggtca tcatccggat 9720 cgcacagccg aggcttgagc atttcgacgt ttgggaagtg acagtcgacg aattgctgga 9780 cttcgccgag tttatccgcg agcgtgcagc ggccgcctgg tcactcaaag ccaaacgcaa 9840 ggcgacgttg aaaggatgcc gatggtgccg ggccgcgcat aattgcgcag cggtggcgta 9900 catgatggaa tgcgccgtcg gtgccgacct cgaattcctg gacactgaat tcggagatta 9960 tgagatgtcg cagttacgct ccgccctggc ggaagaatac aaaatgcgga aggcaaagtt 10020 cggcgatctg tccgttgccg agatggccaa gatcctgccg taccgcaaag tgattgaaaa 10080 ctggttcgcc cgcctggacc tggaacttga gcgggccgcg aaagacggta aggcggttcc 10140 cgggcataag ctggtggaat cacgctctaa ccgtgcgcat accaacgtcg aaaaggccaa 10200 ggagctttat gatttcctcg gccttgacga aaaagactat atgaaaacgg aattgcgctc 10260 gccggcgcag atggaagaag tccttcggga taaacttgga ctgtcacgcg ccggcgcgcc 10320 aatggtcatc gaaagcgtcg tatggaagcc ggaaggcaag ccgaccctgg taccgctcac 10380 tgataagcgg ccaccactgg atcggaaata ttccggcgcc tatgatgacg aagatgacga 10440 tgatgaagtg taaatcggta agatggtaaa cccgtaaatt cgtaacccgg agtagagaaa 10500 tggctgaaaa attaattccc gcgaagaaag ttaaaaacgg cgttctgtat aagagcggtc 10560 acatcaaagt ttccaacgta cgcgcttcat atccgcacct gggcgcccca tacggcggag 10620 acggcgaagg cgagccgaaa tacggtatcg ttgggctttt gccgaagaaa acgcacaaag 10680 agatttacca gctgctgaaa gagcagatcg aagtcgccaa aaagaatcac aaagctggtc 10740 cgctcaaagt ggcgccggcc atgttgttcc tgaaagacgg cgatgtcgat ttcccggaca 10800 aaccggaatg cgctggcatg tgggttctct ctgcgcgcga aagcaaaaag cccgaagtct 10860 ttaacatcga gcgcgaggaa ttaacgacta aggctgagat tgaagaagag atttacggcg 10920 gttgctgggt atccatggtt atccgaccct ggacccagga taacaaatac ggcaaacgcg 10980 taaacgctaa cctgatctct gttttaaagc gtaaagatga cgaaccgttc ggcgaaggtc 11040 gtgttgatac ctccgacgcg tgggatgacg acgaagactg ggaagacgac gaagactggg 11100 aagacgacga cgccggcgac gaagacgacg acgtttaacc cccagcccgt cgggcattga 11160 aaccggaagc ccgcctagtg cgggctttct tataagagga caccatggcc gatattatta 11220 accttgacta cgaaagccgg gcgcgtgcca atctcaaaac gcaaggcctg gaccaatatt 11280 cccgctgccc ggatgcgaaa gtgctgatgg cggcgtattc ccttaacaac ggtaaggtgc 11340 agcacgccga cctatcccgt ggcgcgaaga tgccggcgga gctgaaagaa gcactgcttg 11400 acccctacgt ggagaaatgg gcattcaacg cacaattcga aagggtgatg acccgccgtg 11460 ttcttggtct gaaaaccccg tacaaatcgt ggcgatgcac gatggttctg gcgtacatgc 11520 tcggcttcac tggcgacctt ctgcagatag gtaagcaggt cgggctgaaa gaagaccagc 11580 tgaaagacac ggacggcaag cggctgataa aaatgttctg cgtgcctcaa cgtgtcacca 11640 aaaataaccc ttttgaatgg cgtaacgagc taacggatcc cgaagagtgg tgggggttct 11700 gccggtataa cattcgcgac gttgatactg aaatgctgat caaaaatcgg cttatcaagt 11760 accccatact gccgcaggaa tgggacttat acgccctgga ccagcttatc aatgaccgcg 11820 gcgtaatgat cgacaccgaa ttcgcgcagg ccgcactgga cctggctgaa cgccggaagc 11880 cgcaaatcat agaagagatg aaggatatca ccggccttca aaaccctaac tctgtatccc 11940 agctagtgcc atggcttaaa gagcgagggt acccgtttga cgatgtgcgc caggacacgg 12000 tgaaaaaagt tatccgtgaa caggaagaaa acggcgtcga tgatgaagcg ataaccgttc 12060 tgaaagcccg ccttaacagc gccaaaaact caatcgccaa atataaaacc atgatcgact 12120 gcgccgggga ggacgggcgt ttccgttact ccctgcagtt cgccggcgcc agccgaacaa 12180 atcgctgggc cggacgccgc ctgcagacgc agaacctcgc gcgcaccccg aaatttcttg 12240 agaaagtgga agacctgacg atcgcgaacc ggttcatcgc gaaccgggaa ctggataacc 12300 tggcgctgtt cgccggggaa ccgatggacg cgcttgtcgg ctgcatccgg tcagcaatca 12360 tccccgcgcc gcagcataaa tttatcgtcg ccgacctttc atccatcgaa tcggtagtta 12420 tcggatggtt gaccgactgc aaatggttca tggatacact ggcggcaaag catgacctgt 12480 atcagtcatt tgctgcccac tggctcggaa taccgtacga agacaccctt cctcaccgca 12540 gtaaagccaa acccgctacc ctcggtgcag gttatcgcct tggtggcggc cacctcggcg 12600 atgacgggaa gaaaaccggg ctgtggggat acgcggagaa tatgggcgtt cacatgaccc 12660 agaaagaagc cgcggattcg gtgaaagcgt tccgcgaact ttgcccggaa atagtgaacg 12720 cctggacgca gctggaaaac tgtgtcttcc aggttatccg tacgcaccgt ccggttaagt 12780 ggaaatgcct gaccatcgaa tacaccaagc cattcctgac tattcagctg ccgtcaggcc 12840 gtaagatgta ctacttccgc ccgcgcatcg ctgaacgcca gatgacggtt cagagcggcc 12900 cacgtaaagg cgagaagtac agcacactga acttccagta cgaagggaag attgaaaaat 12960 ccggcggttc gtcctggggc aaagtgttca gccacggggg gaaacttgtg gaaaacatcg 13020 ttcaggccct ggcgcgtgac gtcctcgccg aagggatgaa gaaggcacac cggatgggat 13080 ttaagatcgt catgcacatc cacgatgaga tcgtcaccga agtcccggaa gatagtccgt 13140 taacccttgc tgacctgatc ggctgcatgg cggctgaact gccatgggcg cccggattgc 13200 cgcttggcgc cgccggatgg gaagggtatt tttatcgcaa ggactaattt gcatagaaat 13260 caaagacttg ccggagaaac cgctaatgcc cgaatgggga acccctgtcg tcagggaatc 13320 gaaggtcgaa ggccgctgct gcgagtatgc gcagggccgc ggctggtggg tgtcgaagtt 13380 cacggcacct gggaaaaagg ccgttccgga ccgcgttttt atccggaacg gcgttgtgct 13440 ttttgtggaa ttcaagcgcc cgggcgaaga accaacgctg cagcagcgaa accgccatcg 13500 gcagatgaaa gccaaagggg ctaacgtgac atgggtggac aattttgaag actttaagaa 13560 ctaccttatc tcctttgagt aaggcaatcg cgtattgcca gcgcaacgtg attcaccagc 13620 ggtcggacat gcacggctat caggacgagg gcgtcgactt catcaaagaa acgccgttct 13680 gtggcctgtt cgtcgacctc ggcctgggca agaccgtgat ggccgccact gccgcactag 13740 accgtatcgt agacgggaag gtcaacaaag tgctgatcgt cgggccaaaa cgcgttgcga 13800 aagtgggctg gccaagcgaa ttcgaggaat gggggcacct ctgtttctgg aagatatcgg 13860 tcatcgacgg tgatgcagcg caacgcgagc gcgccgcacg cgaggactgc catttctaca 13920 cggtgagcgt ggataacctc gcgtggctgt gtacgctgtt caaaaagaaa tggccatacg 13980 acatggttat cctggacgag tccagcatgt tcaagtcgca tacctcgcaa cggttcaagc 14040 tgttgcggcg ctgccggccg tacataaact acctggtgga gctgactgcc acccctgccg 14100 ccgaagggta catgggcatt ttcgcacaga cgtacctgct ggacgaaggc gagcgatttg 14160 gcaccacgat caccgggtat caggaaaact atttcatcca gaacaagtac aacttcaagt 14220 tcaagttacg caatggcgcc gaggaagaaa tcatccgtaa gatctccgac atcgtcatgg 14280 tgatgaaggc ggaagattat ctagacgtcg aaaagccaac gctggtaccg ctaccggtag 14340 aactagaccc gcattccgcg gacctgtacc gccagatgga agaagaatcc cttgtcgaaa 14400 tcatgcccga cgaattcgac gaatatctgg atgacccggt gacgattgaa gccgagcagg 14460 cggcggccct gcaggacaaa ttgctgcaac tggcgtccgg atttatctac gataccaaaa 14520 ttgtcgggat caccagtgac gacaaagtag tgaagcagaa agatgcttat cgaattcacg 14580 acctgaaatt cgatgcgctg gaagagttac ttgacagcac cctggagggg gaaaacgtct 14640 ttctggccta tcactttaag ccgaccctgg cccgcctgca ggagcggttc gggaaaaggg 14700 gtctggtcgt catggatgat gacggcaagg cgattaagaa gtggaacgcc ggaaagataa 14760 agctgctggc agcacacccc cagtccgccg gccatgggct taacctgcag cacggtggtc 14820 acatcatcgt atacgttgat aacccgtggt cgcttgaacg gtttctgcaa ttcaatggcc 14880 gcctggcgcg tcagggccag aagcacccgg taacggttta ccagatgaaa gcgatgatcc 14940 gccatccgaa aaccaaggag ctgatcgaca ctgtcgacgg caccgtcatc gaagcgctaa 15000 atactaaggg tgatgtgcaa gatgcttttt ttgatttgct aaaccgcatc aaaggccgca 15060 taactaagcg catgaaggct aagaaaacgg agctatggga tgacgaagac gactaagacc 15120 gccccgctgg cgacccgcaa tcggcgatcg aatgcgccgg acgctgatac cgaggcgatg 15180 attttccagg ggtgcaacat aacgcaactg gcgaagctgt tccgcatgga gcgccgggac 15240 atcacgccga agatcatgga tatcccgccc gtcggggagc gcggcgggta cccaatttac 15300 gccgtccacg aagtcgcgcc gtacctggta aaaccgctgt acgacgtcga gacgtatttg 15360 cgccgcatga acttcaaaga cctgcccaaa gagctgtcga aggagttctg gaacggccag 15420 cgcgcgaagc aggagtatga cctgcgcgca gggaacctgt ggccaacgga agacgtggtc 15480 agcgtattcg gcgaagcgat caaaacgctg cggatgagtc tgctgctgat ccccgacaca 15540 ttatcgcggc aggtagggct taccgaagcg cagcgcaacg tggtgcagtc atcggtggat 15600 tcaatactgg atgacctcgc gaataccctg gaaagacggt tcgcggagga agaagacgat 15660 gaagtttaaa tcgttaaacc acatcatccg gtcggtcgcc agccagctgc ggccaccaat 15720 gcgcatgacg gtcgctgagg cggccgccaa ataccgttac gtgaaccagc ccggcgcata 15780 tgtcgggcct tggcttaata tgaccacgcc atacatggtc gagccgatga acacgctgaa 15840 cagccgccat tacaacaaaa tggcgtttgt cggtccggcg cagagcggga aaacggatgc 15900 gctgatcctc aacggcatta cctattcggt gaaagtagac cccatggata tcatggtgtt 15960 ctgcccgact tctaccgccg cacgcgactt ctcaatgcga cgcgtggacc gactccatcg 16020 gcacagcccg gaagtaggcg ccatgctgat gaagaaccgt gatgccgata acaaattcga 16080 taaacactac accaccggga tcattctgac gcttagttac ccatcggtta cggaactggc 16140 ggggaggccg gtgggccgta tcatcatcac cgactatgac cgtatcgacg atgacatcgg 16200 cggcgacggt aacgcctttg acctcgcatc aaaacgtaca acgaccttcg ggtcgttcgc 16260 catgtgcgcg gcagaatcgt cgccgtcccg cccggtaaaa gacccaaact ggatcaagaa 16320 aacgccgcat gaagcgccac cgtgcgacgg catcgtcggg ctttacaacc gcggcgaccg 16380 ccggcgctgg aaatggccat gcccccattg cgaccagtat ttcgaaggaa cgttccagct 16440 gatgaagtgg gacaccaagt ccgccgatgg ccgaacgctc accaacctgg aaaaagcaga 16500 aacggccaga atggtctgcc catgctgcgg ctgcgaaatc gcgccggaag agaagtacga 16560 gatgaatttg tggggtatgt gggtaccgga aggatgtacg gtaaatgaga aagggcaact 16620 ggtcggcgag ccgattcggg cgacattcgc gtctttctgg ctgcgcggta cggcggcggc 16680 gtttatctca tggcagacgc tggtgctgaa ctacctcgat gcatccgacg actatgagcg 16740 cacgatgtcg gaagagtcgt tgaaaaagtt ctggaacaac gacatgggag aaccctatgt 16800 gccgaagtcg atcgagtcgg ttcgtgttcc ggaaatgctg aaagcccggg cagagccgtg 16860 ggcggaaaaa acggtcccgc ccgccgtacg ttttttggcg gcgacggtgg acgtccagaa 16920 acatcgcttt gaggtggcgg tattcggcgt ggcgccgggg tacccgttcg atatttacct 16980 gattgaccgg ttcaacatca tcaaatcaga gcgtctcgat atagacggcg agcgggagaa 17040 gttaagcccg gcggcgtacc tggaggactg ggatttgatc gagaagcagg tcatgatgaa 17100 gacctatccg ctggccgatg accccagtcg cgtgatgcag gtcaagatga cagcctgtga 17160 ctccggcggt gcagcaggcg taacggccaa tgcgtacgag tattatcgca agctgcgccg 17220 cgaggggaaa aacgggcgat tcatcctggt caaaggcgac cctatgccga aaagcccgcg 17280 tacccatatc gcgacaccgg actctaaccg gaaggacaaa aacgcgatcg cgcgcggcga 17340 cgttccggtg ctgatgataa actccaacat ggtgaaagac atgcttaacg gccgactgga 17400 tgtaacggtt cccggaaaag gcatgtatca tttccctacg tggcttccgg actacgcata 17460 cggcgagatg tgcgccgagc atcgcgacga aaaaggctgg caatgcccgc agggtacccg 17520 aaatgaaacg tgggacttga gttactatct gatcgggatg tgtatcagcg ggcgtgtcct 17580 cgcgatggaa gcaatagact gggataaccc gccagtctgg gctgacgagt gggataaaaa 17640 cccgctggtg gtcacaatag ataaacagga ggccatcgca gaaaaaccag atacaggtta 17700 tagttttgcg caactggccg aaatgttagc atgaggatga ccaccatgac cccagatgaa 17760 tgccgagcca agtaccaaca atggctgaat gacgctatgg acgcctataa ccagctgaac 17820 gtcggtggtt cggtgcgtgt tgtggtggac cagaacggcg aacgcgtaga gtatacggcg 17880 gccaaccgcc agagcctgtg ggcgtatatt ctgcgactgc agaacgcaat taactcaccc 17940 gacccgtgca gagccttctt cggcacgccg agtcgcccag cgaggtttat tttctgatga 18000 gcgaagtcaa gaaagccact cgcgcgagca agaaaaccgc ggttgctacg gtcgacgcct 18060 ctccggcgaa acctgcagcg ggcggcggcc ttgagggtgc tgaacgaaac acccgcgcaa 18120 ccttcaactg gaatcctgcg ataatttcgc cagaccagca gatcgcccgc gataaggata 18180 tggccgatgc ccgcgcacag gacatggtgc agaacgacgg ctatgccttt ggcgccgtgg 18240 cgatccaccg tgacagtatt gtcgggtcac agtacaagct gaacgccaag ccgaattccc 18300 tgatacttgg cgctcctgac ggttgggcgg aggaattcca ggctatcgtt gaatcgcggt 18360 tcaacatggc ggccgagtca ccggaaaact ggttcgacgc ccggcgcgtc aatacgttta 18420 ccggcctggt tcgcctcgcg gtcggcggat ttttgatgac cggggaagtg ctggggtccg 18 480 ccgagtgggt caagtctacc ggacgtggcg cattaggccg ccggccattc ggtaccgcca 18540 ttcagtttat ctcgccctac cgactgtcga acccggacat gcagacggat accgaccgga 18600 tccgtaaggg cgtcgagatt gacgagtatg gcgccccgca ggcgtactgg ttccgcgaag 18660 ccttcccggg agactacacc aacattgaag gccagtggcg ctggaagcgc gagcctgcgc 18720 gattcgactg gggccgccgg cgtattatcc acatcatcga acagctgctg cccgggcaga 18780 cccgcgggat cagcgagatg gtgtcggcgt tgaagcagat gcggatgacc cgtaatttcc 18840 aggaagtcac cctgcagaac gccatcgtta acgcgacgta tgccgccgtt atcgaatccg 18900 aattgccgac gcatgaagtc ttctcgcagc tgggcatggg gcagaccgcc ttttcggaat 18960 acttcaacgc ctacatggcg agtatggccg agtatgtcgc cgcgtcgaag aacatcacga 19020 tcgacggcgt taaagtcccg cacctctttc ccggaacgaa gttcaacctg aaacccgccg 19080 gcacaccggg cggcgtcggt actgactatg aagaatcgct gctgcgcaat atcgccgcgg 19140 cgctcggtct ttcctatgag cagttcagcc gcgactacac gaagacgaac tacagttctg 19200 cgcgtgcgtc gatggcggaa acgtggaaat tcatggagag ccgtaagaag ctggtagccg 19260 accgtttcgc gtctatggtc tatacgctat ggctggaaga agagattaac gccggcaatg 19320 tgccgctgcc accgggcaag acctggcgtg acttttacga cccgatgttc cgtgatgcga 19380 tttgcaatgc tgaatggatc ggagccagcc gtggccagat tgacgagaag aaagaaaccg 19440 aagctgcgat cctgcgtatc aagaatggcc tgtcgacata cgaagccgaa attgcgcgcc 19500 tgggtggcga tttccgttcg gtgtttgagc agcgcgcgcg ggaagaaaat ctgattaaat 19560 cgctggattt ggatttttca ggtaaagttg tcgaaggcgc agagacgaca tcatcttcct 19620 cgtcggcgac cgataaccct gataaggaac agaaccaatg aatgcacatg ttcgatccag 19680 cttaatgcaa gcggttcagc gcatgaacgg gtcgccggta gctgtccgtg aaagcgacac 19740 caatttcctg ctgaatatcc agtcggtgtt ccagatgagc gccgacgagg acgactttga 19800 cctcgatgcc gaagaacgta tcgccacgga gcgcaatcgc aatctatgcg cggcttacgg 19860 catggcaccg tcgagcggaa ataaaccttt cgccttttcc ggcggcttcg ccatcatccc 19920 gatccacggc tccctgatta accgctatgg cggctattac tatggctacg tgacgggata 19980 caatttcatc cgctcgcaga tgaacgccgc actggcagat cctgacgtgg aagctattat 20040 tttcgacgtg aactctaacg gcggcgaagc agcgggctgt tttgagctgg cgaacgagat 20100 tttcgcatcc cgcgcagtga agccgtcatt cgctgtcgtg gactccaatg cgtactctgc 20160 ggcttacgcc ctgggcagcg cagcgacgaa aatggcggtc attccgtcgg gcggcgccgg 20220 gtccatcggg gttatctcga tgcacgtcga tatcagtaag atgttggaag acttcggcgt 20 280 taaggttagt attattaaat ccggtgcgca caaagccgac ggcaacccgt tcgaatcgct 20340 ttccgatgag acaaaagccc gctggcaggc agatgtcgac accatgcgtg aagacttcgt 20400 caatcttgtc gcacaaaacc gaaatttaga tccgaaagtc gtgcgtgaca ccgaggcatt 20460 atgctataac gccccagaag cactggccct cggactaata gatgcggtca caacgccggc 20520 taaggcagtg gctgaattcc taaacgggcc gtccggtggc tcggatgaac aaccaggagc 20580 aaacgcgatg tttacccaag aacaaatgga cgctgcccgt caagatgcag cagccgaagc 20640 aactgccacg gctaccgcgg cagcgactac ggcggaacgt aatcgcattt ccggtattct 20700 gggatgcgaa gcggcgaaag gccgttcaaa actggcgtca catattgcgt tcaacaccgc 20760 aatgagtgtt gccgatgctg aaaccatgct gggcgcttct gcggtcgagc aggccccggc 20820 atccgcagcg gctaccaatc agccggagaa aggggcagac agcccgttca agacggtgat 20880 ggataacgct gaccacccga atatgggtgc ggaaaacgaa cagcaggctg aacccggcaa 20940 aggtgatggc ctgatggctg cgatggccgc tgtagctggc gactcgttca ctaagtaaga 21000 ggcgactaac atgtctttga tctccctgat ggcaagcctc ccgaactatc tcgctggcaa 21060 cggcgacctt ggttcgtggg aacccactca gctgtttgct ggtgaagctg atatcgtaac 21120 cgacggcggt gaagtcgcag tcgcgtttgc gcgttatcag gtcatcgcca aaaacgcagc 21180 tggcaaactg gtgccttatg acccgaccac tccggccaac ccggaagcga cggccatcgg 21240 tatcgctaac gaagctggtg tcgtgggaac ctacgcaccg tattacatcg gtggtgtgtt 21300 caaccacgaa gcactcgtat ggccagcagc agtcgacact ctgctgaaac gtcaggcggt 21360 gttcgaacgt acgaacatcc acatcggcaa cctgtactaa ggagcagcag aaatggctgg 21420 attgtacgaa actaccgtcc tgatgggagt gcaacgcaag gttaagtccc tgccggcgtt 21480 cttcctgcag tggttcccgc gccagattaa cttcgaggaa gaccagatcg cgttcgataa 21540 ggtcatccag gacgttaccc gcgtcgcgcc gtttgtcgca cctaccgcgc aaggccgtgt 21600 gatcaaggaa caaggttaca acaccaagac cttcaaaccg gcttacgtta aaccgaagca 21660 cgtcattgac ccgaacatga tcgttccgcg tcaacccggc gaagcgctcg gtaccggtag 21720 cctctctaac gagcagcgtc gtgaccgtgt tatcgcattc ctgctgatga agcaccgcgc 21780 gatgcatgaa aacacctggg agtggatggc cgcgcaggct gcgcagtacg gctatgttga 21840 cgtggaaggg caggattacc cgaaaacccg cgtagacttt ggccgtgatg cggcgctgac 21900 catgacttcc gactggaccg ccaccggcgt taccctgatg gacatgatcg ccgacctgcg 21960 cgatggccag cgtctggtgt ccgataagtc actttccggc acggtgatcc gcgattacgt 22020 gttcggcggc gacgcatggg accagttcgt taaagtcggc ggcgcagagc tgtggggcaa 22080 agacggcctg atggatggca atatccgcgg ttccgactcc aacctgaccc gtctgtggga 22140 cgatgtcgaa ggtgttcagc tcatgggtga actggtaggc atcaacggcg ccggccgtat 22200 gcgtttctgg gttaacactc agaaattccg cgactggaaa aatcaggaac agtacctgat 22260 gaaccagaag gccgtcatgg gcatctcgtc tgcgattgaa ggcgttaagt gcttcggtgc 22320 aatcatggat aaagcggccg gctatcgggc gctggaatac ttcccgaaaa tgtgggaaga 22380 agaggatccg agcgtggaat acctgatgac tcagggcgca ccgctgatgg tcccggcaga 22440 cccgaatgcg tcgttcctgc tgaccgtcgt tccgtaacca cctgcaggcc cgtcaataat 22500 ggcgggccaa tttaaaggac agagattatg ccacaacgta aagtagtcca gacggtcatc 22560 gttttccgcg acggccagcg tatccgcccg gcgatcggtg aaatcttcaa cttcacccag 22620 aaagagctgg aatccatcaa cagcatgaac ccgggcgccc ttgaccgtcc tgtcatcgaa 22680 gtcgatgcgg aagagcaggc ggcgaaagag aaagcgcctg cgcaggaaga aaagtctgac 22740 gcgaaagcca ccaccaaaaa aggcggtaag gccggcgcag cggacgaaga ggtctgatat 22800 ggcctctaac ttcgcggcaa tcaaagcgaa ggcacgcagg gacgttcacg cgtccctgtc 22860 tgtatctgcg cggtatgaaa gctattcgca ggaagtcatc gtcgacggtc ttagcgtgcg 22920 ctggcacaac aagcagcaac tggtcggcga tctggatagt ggcggttacg cccagattat 22980 cgatggcatc gagcgaatcg tttttatgca ggacgagctg caggagaaag gcgtcacgct 23040 ggaaggcggt gatgtgatta tcatcacggc ggaaggatac ggcaacgttg gcctggtgct 23100 acagacgcag gaaccgattg tcggtccggt cgaagtgatc tggcaggtgt cgaggaagaa 23160 ctgatgaccg ttaacgttat ttccgtgggc gacctggagc tgcgtgacta tctcaagcgg 23220 cttccggaaa taaccgaact ggcgatgcag atggccatta acaccgtcgc atcgcgcacc 23280 ggcatgtcgt tggtcaagaa aaacatgctg aacgaggtgg ccttcccatc cgggtatctc 23340 aaccccgacc gcctgaaagt caccaagcgc gccaccagaa ccaacctcga agccaccatc 23400 accggacgta aacgggcgac ctccctggcc cggttcgtga cgagtaacag tgttgtgaac 23460 agccggcgaa aggaaggggt atccgttcga gtgaagcgcg gtaagaccac gtacctgaaa 23520 aacgcctttc tcgtcaggct gaaaaaaggc gccagtcttt ccgaagacaa ctacaacatc 23580 ggccttgccg taaggctttc cgccggggag tcattatcga ataagcggac gcagcataaa 23640 tcatggctgg ttccgggcaa ggtggcgttg ctgtatggcc cttcggtaga ccaggtattc 23700 tcggaggtgg ccgagaaggt cgggtcgcaa attgctgaca tggtggcgac ggagtttttc 23760 cgtaatttcg agaggttatc atgagtaagc gcctcgatgt gctgaaagca ttaacggatt 23820 tcctggaagg catttccccg gataacgggt atccgtatga cttccgggga aaggtgtacc 23880 gcggtcggga ccgtttcggc gcggaatacg tggcaaagat gccgttcctg tctattctgg 23940 aagcgaaagc aaccgactac gggaagttcg ctaacgagga acagaccgtc cggatggatg 24000 actgggtgct gctggttcag gggtggtgcg cagatgacgc gcgcaaccca acggacccga 24060 tttacgacat cgtggcagtc gttgaaaagc gcctgtcaat gctcatctcg aaggatgaaa 24120 atggaaaccc ggaattcccg ggggtctatc ggttaaaggg aatgattgct acactgacac 24180 tcgcacagcc ggttgttcgt ccgcccgagg aaggactatc ggacacggcg tttttcttcc 24240 tgcctattag ggtaggacta aaagtagata ttcggaatcc ctaacaggag atgaaagatg 24300 caaagcgatt tccagaacga ctatacgatc ggacgtggga aaacctattt cgataagttc 24360 ttgccgaact ctaaccgcaa gactggcgaa atgtacttcg gcaacggccc ggaattcacg 24420 atcaccactg atacggaaaa cctggaccac tatgcgtcgg attacggcct gcgcgtaaaa 24 480 gatgcctccg tcctgctgga agccggcatg accgggactt tcacctgcga caacatcgcg 24540 gcggagaacc tggcgctgtg gttccttggc gacctggtta acatgaccct gaccgaccag 24600 accggcgtca aggaagtgtt caagccggta ctgcgcggta agtattacca gatcggtacc 24660 agcgacgaca cccctaccgg cctgttcaac gtggataacg ttgtggtcgg cgtggcggat 24720 ggtgacgctg aaatcgtccc gggaaccggc gatattagcg gcctggcagg cgtgaccatc 24780 gttaccgccg ctggcaacta cgagctggac ctggcgcaag gccgtatcta catcgagccg 24840 gactccaccg agttcgcggg taacaagcag atgatcatcc agtgcgatat cgctgcgcag 24900 aaccgcaaca tggtgatcgg caagaccaat cagatttacg gcgccctgcg ttacatcgcg 24960 gacaacccgg tcggtaccaa caaaaactac tacttcccga aagtggcgct gcgcccggac 25020 ggggattatg cgctgaaagg cgacgactgg aacgtgatgt cgttctcgtt cgaagcgctg 25080 cagctgaaca acctcaccca gcgtctgtac attgacgtgc tgccgtctgc ggcaaccgtt 25140 gacccgacga cgctgcgtac cgtgtctgta tcgctggcga gcacttcggc ggcgtccggc 25200 ggtgcgggta tcgtggctac cgctacggtt cgtgacggca acggcaccgt ggttcagggt 25260 gaaaccgtga acttcacgac ggacaccggc gctaccgtta ccccggcgag cgcgtccacc 25320 gcgagcacgg gcctggcaac caccacgctg aaccgcgcga cggccggtac cgccaaagtt 25380 accgcaacgc tggcgaacgg caagtccgca gtatcgcaaa ctgcgacctt ctcgtaagag 25440 cagaccgcag tcacaccgga aagcgcctac gggcgctttt cttttatgct tttctgccga 25500 cgtgctacat taacgacgtc aaccaacgaa gaggataaac cccatgtcac tgtcagattt 25560 caccccggat accgaagaaa tcatcgttaa gcgcgctaaa aaaggcgata tgacattcga 25620 ggtccgcggc ctttccttcc aggacatttc gaagatcgtc cgcgtgcatt atgacgacct 25680 ggaagggctg tttgatattt acgaaaccca cggcggcggc gacctttcct acgtggccat 25740 gggcaaattc gccatgggtc tgattaacga tgcgcccggc ctggtagcgc acatcatcgc 25800 gctggcggca gacgacgaag ccaacctgga gaaagcccag cgcctgccgc tgaccgccca 25860 gattgacgcg ctgaaagccg ttggccgcct gaccttctcg gacgttgaag atataaaaaa 25920 gatgctacga aaggccatgg acctgatgag ggaaacaaag gcaagccgga cacccgcgtc 25980 tacagcaaaa gggaaaaagt aatccggttt cacaacgagc tgcgggaagg cgtgtccttc 26040 ctgatgtctc agggacaccc agacgcacgc cggtacccgc tggggtacct gtggtctgaa 26100 atcaagattg cccggcgccg cgtgaatatg cacctggtga cggaaagcac gttactgcag 26160 gcgctactgg cctccgtcat gaacgggaag aaaggtggcc cgcactacaa aaaactgatt 26220 aagggcttga gcgatggcta acagcaaaga cgtcgaacta aggatccggg cgagggattt 26280 cagccagaaa cccctgaaag ccgtggcctc cgcgattgaa gcaatggcga aggcgcagga 26340 cgaccagcgt aaagcggcgg aacggggaga agtctcgacg cgtcagctgg aagcctcgta 26400 caaaaaactt gagcaggccg ggcagcagct gttaaagctg aatgccctgg tggagctgta 26460 caaacgccag aacgccacga tggttgaagc ggcgcaaaag acggaagact tacgggccaa 26520 gcaggcgcag ttgcagcaag cgtatgattc atccacgaag gtaactaaaa aacaggaagc 26580 cgaacttgcc cgtatcaacc gtcaggttga gcgcgcagaa cgcgccgagg cgtcacgcgc 26640 cgcgcaggtg agccggacta ccaaagaact gcagcgatac ggtattgaga cgaaaaacct 26700 tggtgccgcg cagtccagca tcgttaacag cgtggcgagc gttaacaagg tactgcagca 26760 gcaggaaaac atcatcgcta ccgcgcctgc ggcggccgcc caaaataaag tcatacaggg 26820 actgcagcag caagcgcagc aggcactggc ggcggcaaaa gggtattcaa ccctgggccg 26880 ggtcgtacag accaccacgt cgcagatggg gccactggcg tcgcaaatcc agcaaatcgt 26940 aagcccgtca gacgctgcgc gccggacgct gtctggactg cagcagcagg tgacaaccct 27000 tgcgacggag atagcgaata gcggcaaaaa gattaccgat atcacaggga agatccgcca 27060 gctgaatgac gcgaataaaa gtgtttcggc catggcgcac cagatcgata tgtaccgtca 27120 gcaggtggca gcgatccggg cagcgcgggc ggaataccgc acagcaatgg gggcggtaca 27180 gggtttagcg cagcagatgc gaacggccac taccgacacg ggtgaattgt cggtccggat 27240 gcaggcggca cagcagagac ttgcggcggc cgcccggtca ttgcgggaca ccgggactgc 27300 tgcgcgcacg acacaatcgg ctttgcgggc ggcaggcatt gatacccgta atttgaatag 27360 cgccgagcag gcgctgatct ccacaagccg tcagaccacc agttctataa actccctaac 27420 gcaagcattg cggaataacg cgggcgccac gcgcgacggt tcaaaagcct tctctctttt 27480 ccgcgatgag ggacgaacta cgttatcaat gctgcagcgt atccgcggtg aggtcctggg 27540 gctggccacg gcctatgttg gtgtgcaggg ggcgcttaat caggcatccg gtgcggtgga 27600 tgcgtacaag atgcgtcagc aagccctggt taagatctcc accgttgttg gggaaagcca 27660 ggcggcactt aacgacgaat ggcaatatat gctcgggctt tccgacaagc tgggtattga 27720 tatcggagtg gtcgcgaact cgtatacccg gttcgcggta gcggcgaaag ccgtcggtct 27780 gtcgttgcag gattcaaaat tcatattcga aagcgtggcg aaagccggcc gtgttttcca 27840 cctctccgcg gatgacatga acggtatttt ccgcgcactg gaacagatgc tgtcgaaagg 27900 gcaggtttac gccgaagaac tgcgcggcca gctgggcgaa cgtttacccg gggcggtggc 27960 gctgttcgcg aaaggtatga acatgaccac gacgcagctg atgaaggcaa tggagaacgg 28020 cgaggtttcc ggcgaagcgg ttatcaactt cgcccgtgaa caggctaagg ctattgatgc 28080 ccagctggaa accgcgagca aaggcgtgga cgcgatggaa gcccgcgcac gtaacgcgat 28140 gaatgcattc cagctggcgt tagcggactc cggatatatc gatgcatacg ttcagctgct 28200 gcagaaggtc acggacttcc ttaatagctc ggatgggagg gaggccgcgg taaaactggg 28260 tgcggcattc agctacgtgg cggacactct agggtatctg attgacaacc tggacacggt 28320 tatcacggtg ctcggcgttc tggccggcct taaaatcacg cggatggttc tggggttagt 28380 cgggtccatc cgcacgatgt tgccgatgct gaaagaaggc gtcgttctca tccgcggggt 28440 atacactggc cttatgacat gggcgaccgg tcttgcgacg gttgaaggcg cggtcggact 28500 tctcggcgtc gcgttacgcg ggctgctgcg cgttatcccg tttgttggcg cagcgcttat 28560 cgcgtacgac atcgggtcga tcatgtacga ccagtcgtcg accttccggc agggcgttga 28620 cgaggtcatc cgggattaca aaaacctcgg caatcagctg ctggcggtcg gggagtccat 28680 cccgacgatg ctgtacgaca tcctgatcgg ctgggtacga cccgtaacga cgcaattcgc 28740 cacggccacg aagatgatca tgggttggat tgccaatgtg ttgcgcctga tccccggtgt 28800 cggcgaaacg ctggcgaact gggcggatac cctggccgaa gacatgacca aagagcaccg 28860 tgacttcctg gagtccacgg gcaaggtctg ggatgacgtc gataaaaaat gggccgagtt 28920 aaataaaaac atggtcgaca ccaacaagac tgcggtggat gttatccgtg gtcaggtggc 28980 gatgctgatg gccgatatta aggcgatcac aaaccctcaa ttccagtaca ccgctgaccc 29040 ggaaactgga gtcacccagc gcgaccgcga catcaaaggc atgacgaaag accttgccaa 29100 gatggaagaa caggcgaaaa aggctggcgt tgccgcgcag aaagcactgc agcgtaaaaa 29160 cctgccaggc cgcctggcga ttatcgatga ggaatttgcg ccgcagtacg cccgtgccaa 29220 gtcgatcggc ggtgacgaag gtgctgcgat gaccaagcgt ctcgacgcta ttgtggctgc 29280 gcggaagaaa gccgagacgg attcctataa cgccatggaa aacggcagca agggcagggc 29340 gaacgcggcg aagcgggagg aaaacgcgct ggcggcgctg acctctcagt atgaaaaact 29400 ggatgatgcc gttggcgtca agcagtcgaa ggtcgacccg aatgcctcgt ttgatgaccg 29460 actgcaggcc aaactgcagg ccgttaatac ccagtacgac cagctgatcg ccaaggcgaa 29520 aaaactcggt tcgggcgggg cagaactggc cggcaagttt gaagacctgc gcaagcggaa 29580 tctcgaatat gctaccacgc aggcgaagct ggaagagatc aagcgcgtgg aggaccagct 29640 taacgcggtc caggaaacga agaaaagcct gctggatgag ataaacgcca aacgtcaggc 29700 gggcattatc tccgaagatg aggcggtgaa gcagacgtcc gagctgtatg cgacgatgaa 29760 cgtgaacctg cagcagtcgg cgaacacact ggaccagctg gcgcagaaat tccgcaatgt 29820 tatgtcgccg gaagactatg cggcgctcat ggccaaaatt gcgcagatcc gcgcgggcct 29880 gaatgacgtc accggtacct ttacccagat ggatagtacg gtggtgcagg gcgttctgga 29940 tgggctggcg acgggtctac agtcggtcac ggatagcctt gtccaagtcc ttagtggcac 30000 gatgtccctg caggacgcat tccggagcct cggcgctacc gttaccaagt tcttcgcgga 30060 cttcctgatg aagattgcgc aggcgatcct gcagcagatg gtactaaact ccctggcggg 30120 aatgggcggc ggtatcggtg cagcagcggc atcgcttggc ggtgtagcag cgaaacacaa 30180 cggcggcatg gtcggcagca aaacgacggg cggccagcag cggaaaaact ccgtcagccc 30240 gtcgttgttt gtcggggcgc cgcgcttcca tgacggcggc ctgcccgggc ttaaatcgga 30300 cgaggtgcca atcatcgcgc agaaaggcga acagatcctg tccaaagacg acccgaataa 30360 tataatgaac caggggggcg gtagcggcag tggttccggg tcatctaatc tgcaggatat 30420 cagggtcatc aatgcgatag attcggcatc ggttgtcgcc gccgggctaa gtgctccgga 30 480 aaatagtaaa gtggtcctca acttcatcaa ggccaataaa caggctgtta aacaaattct 30540 ggggtgatga atggcgagct taaccgacaa tgatgcactg gtcagcagtg atgggctggt 30600 agcgcacagc cttacggatt cgacgactga cgcatcgggc attaatccgg cggcgggaac 30660 gtcgtcggaa cagttccgga tggtgaccgg acttctgcgg gcgcaccgta ttgctccccg 30720 cccggcggcg gtacaactgg caaatcgcat cctgactgca gctgtatcct acctctaccg 30780 tggccagtcg tcagaagccg ggacgtttat cccacactat ctcgtcggcg tccgccataa 30840 cttcacgttg ggtaatggcg acgtggtgca gcccggagac gcataccgta tcgccccgac 30900 ggtggagatt gagccgagta ccgataccga ctcggaaaac catgctttcc gtgatgcgta 30960 tgaagccttc tcgatcggct ccgacgtaat gggggagaac gcctggacgc tcgcaaagga 31020 cgctaccgag cgccagatta aagggtcgat tcgatactcc gggttgtggt atacgccggg 31080 cgcggtaccg gtcattacgc agttcactcc gaatgataat gggtggcggc cgccggcgta 31140 cgttggtcgg cagatagggg cgcagtgggc gtcattcggg gatgcggaag ccaccgacaa 31200 taccgtgttc atgatgaacg acgcacagga cgcatggacc gcgcagaccg gaaaaatcga 31260 tggccttttc atgccggtgt tctacttcga ctctcccggg tcgacctcgt acggcccggc 31320 gaacacgttt gggtggaatg gccccttcga ctcacagagc atgtacgaac agctgtcggc 31380 gatgcgggat gccgttcgca tcgctacaca ggcaggcgag gcgggccgta aagcctacgc 31440 aacggctatc gctacccgtg cgcttaaatg gttcgggaat gaccgcaact ggatcccgtc 31500 gaacccgggc atcgcagacg cctggagcgc ggcgatccgc aaagcggccg ttctggggta 31560 ccaggagggg gataccgtta cgctgcctga actctggttc accgtcccga atcgcctgaa 31620 taccgatggc tcattcccga cgcctgtcta tgagccgggg ctactggcgg tggcgctgca 31680 ggcggcgatc gcggtggata agctgcagcg gccaaacaat gccgcaggtt cgctgtctac 31740 cgaagtggcg cgcgtggtag aaaagtgcat ccagatgttc gacttcacct acgtgaccag 31800 cggagtaatg gccggcacat tcagcccgga cccggcgaac cttaaatggc aagggcgctg 31860 gcatgcggaa ctgctgaatg ccatggtgga cctgtatgac tggtgtgggc agtcgaacaa 31920 taactacacc gccacgcggg cgaaggcgcg agagtggatt acggggctac tggactcggc 31980 ggaagcgcta tcggcagacc agtctggcgg attcatctat ggtcggtcta tgtggccgct 32040 gcagccaaac tggaaagacg gcatgacgga gtcgttcgaa ttttccacgc agatcatcac 32100 ggcggccagt ggcaaagagc agcgcttgtc ccgtcgcacc aaaccgcgcc gggcgctgtc 32160 catgcgccat acgctgacga cggcagacga ggcggcgcag tatcaggcca tcctccggaa 32220 gcgccagtgg cggccaatgc ttgttccgca gtggcacatg gcatcccgca cgctggtagc 32280 cgggaaagtc ggcgatacca ccctggtcct ggacaaagag ccgccggcca cctggggtgt 32340 ggtgaaagcg ctgtacctcg tatcagggga tgaccgccag ctgcttaacg tgctgcgggt 32400 atccgggtcg acggttatgc tgcgcgattc gctgacgttc ccggtaccgc gagggtcaga 32460 tattatgccg gtgcagtacg ggctgctgaa taacgacctg tcgtcttccc gggcgatctc 32520 caccacgatc gaagcgcagg tcggtttcac gatcctgccg cagacggact cgtttaccgt 32580 gccggcggta tcatcgtaca acgacctgat ttcgtttatc gcggaacagg gccatcgctg 32640 ggcgaaatat atccgacggg ccgccgcgct tgatcccgca gtatggccga cgtggccgcc 32700 aatgccgtcg aactatacga cgcgaatgac ctttgaactg aacggcgata cccgcatggt 32760 catcacccgt aaacctaact gggtatccgc ggtgacagtg gccgacgcct ggcagtacga 32820 cctgatcgac tattacaact cggcggttac gccggggtat gcggagaacg ccggacgccg 32880 tacattccag gcgcagtgga ccgcattcac gtatgatgag gttatcgata tcctcgcggt 32940 attctacgcg ctgcgtggta cgcaggtggc ctgctgggta ccatcgtggt cccacgacct 33000 gacggcggca gaggatatgc cggcgccgaa tcagttacga gtggagcgga acgccgtcat 33060 tgacgaagaa atattgcttg acgacccgag tatcgcattg atggttgaaa cgtttgatgg 33120 ccgcatgtat tgcgcggcgg ctaccggggt aacaacgtca gtcggggtat cgactatcac 33180 actggaccgc gagttcctca gcccgctcaa aaaggcggac atgatgcgga tcagcctgat 33240 gtaccgtgta cggcaggcca gtgattcggt ggaactttca tggcatgccc gcggcattgc 33300 cgaattgcag acggccttca tcaccgtcca ggagtaaaac gtgtcatatc ctcaacttga 33360 agacagcgtt gacagcggga aaccgctgta tttttacgag ttcatttacg gcgatgcagc 33420 gacgaatgcg taccgttatg tcgccgcact ggacctcact atctacggcg gccgcccatg 33480 gacccctttc ccgataaagc acagcgatat cgttacatcg gggtcactgg ataagcagac 33540 gctgacggtg acggcgcggg aggatattga tattaccgga ctggtagtga cccgcgcgcc 33600 aagccgggta acgatgctga atatctaccg cggccacgct ggcgatgatg acatgcggat 33660 ggtctggacc gggcgcgtcc tgtccggcaa catgatagag tcgtccgagg tggaactggc 33720 ctgcgagtcc ataagcacat cgcagctgaa tattggtctg cggcgtaagt atcaacgcgg 33780 atgcccgcac gccctttatg gtcgggcctg ttcagctgat aaggcgttgc attcggagac 33840 cggttcgtcc acggcggtcg ctaattcaat gacggtgtcc gttaccctga cgagtgaaga 33900 ccgcgggctg accgaggcta ccctaaccgg tggtatcttc cgcatcacgt tgaagaacgg 33960 cctgaccgaa atccgggcga tctcgtctgc gataaacaac ggcggccgca actggacgtt 34020 aaatatcatc gcgcctattt ccgacatgac cgccggccgt ccggtttctg tatcaaaagg 34080 ttgcctgcat acatacgatg cgtgtaaaaa cgtgtttaac aatgcggata actatggcgg 34140 atgtgccaat atccctatca aaaacccgtt caatgcaaac cagttctagg gggcgccatg 34200 ccagattggg tcgtctatat aattatttcc atcgcgatgt cgctggccag ttacgccctg 34260 actccgcgtg caaaaacgtc cagcgctaac cagtcaccgc agacggtcga cgtgccgacg 34320 gtcgatgcgg gccggtccat ccccgtagtc ttcgggacgg tgcgggtgaa atcgcctaac 34380 ctgttatgga tgggcggaca acggacaacg gagatcaaga aatgagtgat atccgcgtat 34440 tacctactga cctgccgacg gcgggtcttt gcgttaatgg cgctcgcgac tggttcgcga 34500 aacatgggct ggacttccgg gacttcatta agaatggcac tccagtagat gtcatgcggg 34560 cgaccggttg cccactggcg gaacgtgctt gccaggccgc cgagaagcgc gtcaacggag 34620 ataactgatg ggcgggaaaa gcaagaaaaa atcggtcgtc ggctataagt acaacatcgg 34680 cctgcatttc gccatttgtc acggtccgat cgccaagctg caggaaatct ggtgggcgga 34740 taaggtcgcc tggtccggca cgttgaataa ccccggggac gagtcgcagg ggcttgtggc 34800 ggtggacaat accggcctgt ttggcgggga ttcctccgaa ggcggcgtga aagggctggt 34860 ggaaatcggc ttcggtggat gggggcagcg ctgtatcggc gttggatccg acgggtcgta 34920 ttccgcgcca gccatcctgg cctggttcat ctccaaagga tacaactgga agccgcaggt 34980 taaggtgccg gacctcggcc tgaattaccg tgggctggcg gtcgcgctga tgcatgacca 35040 ctacatcggg aacaacgcct acctgaaaga cgtgtcgttc aaggtcagct gcttctgggc 35100 cgactggcac cctgaacttt gctacatcgg cgataacatg aacccggcgc acatcatccg 35160 cgaaggactg gtgaacacgg aatggggtct gggatacgcg ccagccacga tcgatgacgc 35220 cgcatatctt tctgccgcgc agactctgta taacgagggc ttcgggctat ccttcgtctg 35280 ggatgacgac aaagacctct acaccttcat tgacgaggtg aagtcatgca ttaacgccgt 35340 gacgtatctc gatccgcgtt ccgggctatg gacgattaaa cttatccgcg ctggcgagcc 35400 atcggcgctg accatcaacc ccgacaacgc cagcctgaaa tcctttaccc ggaaagcgct 35460 gggcgaaacg tacaacgaga taagcacgaa gtacacgaac ccggaaaacg aagagtacga 35520 gacagttacc gttcaggacc cggctaacat cgaggcgcag ggccgtgttg tgtcgacgac 35580 gaaagagtat gtcggcgtgc gggatgcaaa cctggccatc cggcttaccg aacgtgacct 35640 gcaggtggcc agcgcgcagc tgtgtacagc cgaggtgacg gtgaaccgcg aagcgtgggc 35700 catcgcgccg gggatgaacg ttaccttcaa ctggccgaga cacggcatct cgaacatgat 35760 catgcgtgtc gaagaggtga gcattgctgc tgtcggggat gactcgatct ccctgcgcat 35820 cgtggaggac gtcttctcgc gctcatcggc gaccttcgcc ggctcgcagg ataacggctg 35880 ggtcgacccg gcacaaccgg caacgttgtt cccgtaccgc cattcctggg agtatccgtt 35940 ctggtatctt attcgcgctg caggtctgcc agcagacgtc ctgccgacct tcgccggatt 36000 ctcgacggag attgctaccg gcggcaacga taacgcgcaa tcggtccagc tgttctccta 36060 catcaccacg gacgctggtc catcgtggca gctggtcgca gttggaccgc tgacgccgaa 36120 atccgcgttg tccgatgcgc tggttccgga aatcacctcc ctgatgaagc tgaatacgtc 36180 ggccagctac cgcctggcgg acatggagac gaacagtttt gcgcttctca cggatggtac 36240 caacgaagag atcgtccagg tgacgaactt cgcggatgtc gcgcagcagg cgaccattac 36300 ccgcggcctg atggacacac aaccgcgtaa ctggccggcg gggaccatcg tgtacttcat 36360 cggctccagt tccttcccgg aagacgagtc agtcaggtca ttcggcgaga cggtgcaata 36420 ccggccagtg atgcagacct ccattgacca gatggacatt aataacgttc cgacggatac 36480 catcaccctg cgcgggcggt acgagttgcc gtacccggtt gccaatgtga agatcggcgg 36540 cgcatactgg ccagtgtcgg taaacgtcaa tggcattgac ctcgccgtca cctgggccaa 36600 ccgaaaccgt ctgctgcagg acgcggctac ccaggtacca tgggacgccg gaaacatcat 36660 cccggaagac ggaaccacgg tgacgatcga gctgtggcgc agcggctcaa tggtgtacca 36720 gcagcaaggc atcaccggca cgtcgtttaa catccctgtg gatgccctgt cgaccggctc 36780 ccatgagatc cgcatttaca ccgtgcgcga cggccgccgg aactatacta atttccagca 36840 cacttttaac gtcgtactcc cgtctcgcga tacggggtat ggcaatagtt acggattcac 36900 ttacggagta taaccatggc gcagaaaacg gccccgaacc tgggcatgac ctacggctgg 36960 gatttaggcg aaagcgggtg gaagcctggt atggatgcca acatgaaaaa actggatgca 37020 attgtgggcg ccgcggtgct ggccattgcg aacagtccgt cagttacgga tgacggaacg 37080 cgctacattg tcgggacgtc gccgtccggc gcctttgccg gccaggcggg gaagctggcc 37140 gtacgtgttg aaggcgcatg ggaattctat acgccccggg caggatggtc cgtttacaac 37200 ctggcgaatg gcacggcgta ccggtacact ggttctgcat ggattatccc tgcgattgcg 37260 atccccgcac agccattcct ggaagtatct ggacccggta ccgaaacctt tgataatact 37320 gcgtgggtga aagttccgct gaccgtcatc gcgtcggata cggcagacgg gtgggatgca 37380 acggccaaca ccgactacat catcccgcag gccggcatgt accagattca ggggattgtc 37440 cggcccgcgc gaaccggaag caaccctttc ccggattcaa cggcattcgc cgttggggtc 37500 ggggccacgc cggcagacgg ggatgacgtg gcatgggcgg ttagcccgga cgtggccggc 37560 gcgcagttta ccctgcaggt agccgtattg cggcgctata atgtggggga ccgagtatcg 37620 ctttttgtga aacattctgc gacttctcct gtcgctattt cgcgcgcccg cttacgtgtt 37680 ttgcgtttaa cggattaaat gcgggatgct atagtgggca aacggttaat cgagggtaac 37740 taaaatgtca gatatggacc cgttgtatga attgatgaaa gactcagcgg aggatatgtc 37800 caaggctgtg gttgaaatga aggatatgat gacggaggac caaaacaccg acgtcgtcgt 37860 cgaagggtac ggcccgaagc cttcattcag caaacagata aaagagctgg tggccgggag 37920 gtcagaaggc atatttcggc tgtatgcgac attggccgag gcccaggcgg atatcgcgaa 37980 tacccctgtg gggtctgtaa cctatgtccg gggggcggat agcacgtccc tggccgatga 38040 gtatatcaac aatggcggca ccctaactgc gaccggacgg acgatgccat ccggggtcgc 38100 cgttgagatc atgtccgcta ccgtccagcg tttaatgacg gctttgcacg ttatggcgga 38160 gggcgacgcc ggttcggttt caggtattga cagcagcgat actgtgcagg gcttgatgac 38220 cggattcaac gtactggcgg agtcctttaa taacctttca gtggaaagtc agaaaaatgc 38280 ctccggcctg tccgccctgg tctcatccgt ccagatctgc actgaagcac tgaatacgct 38340 ggcggcccgg gtcgtgaccc cagacggcgc gtcgcagtat gactatatgg cattttccac 38400 gccaggtacc gtcaacgcca gtaacgggac gttcggtagc aacacccaat accgcaggac 38460 cgggatgatc ccggttcgca agggcgacgt tgtacgcctc accgttcaca ccgcaacgac 38520 agtcgcaggc cacgccgccg cattatatga cacagcggga acgtatgtgg gtcccctggg 38580 gatcatgtgc gggacgtatg cggcgtataa ggcgcggtat taccagtgtg aaattaccca 38640 ggatggattt gttgtcgcaa acacgctgga ccagagcgcg tccccttctg cagatgtaac 38700 aggtgcgtca ctgacgattg accatcgtct tcgtggccgg gaagcagaca cggttattaa 38760 gctgacaaag tctgatttga tcccggtccg cctggataac gggaacatca acgccagttc 38820 actcacccag gacggaatcg ttaactattc caccgggctg tattcctgca ccggcggcag 38880 actcctgttc agcggtttac ctgtggcctc atctccgggc cagagcagca gcctctacaa 38940 cgtcgtgttt tatgacgccg ctaaagcgct gatcgcgtac cgccccgtgt tctccagttc 39000 gggctatgtg gttatccccg aaaatgccgc gtactgggcg cagcagataa tcaccgacag 39060 aacacccaac tggtccgagg tctcgatagt ttattacaac tacgtctaca aggatgagtt 39120 gcataagcta ctgtcatcag aacgtgagcg cctcggacgt aactacccta acgaatattg 39180 gctgcaggat ttcagcggca ctaccgatat tgagtggatc cagaacgcaa tggactgggt 39240 gcatgatgct ggtggcgggt ggttgatact gtcatcggat tatgtgaaga aacagttcat 39300 catctccgaa gcggttatcc accgtagcaa tgtgtgggta gttctcgatg gtgtcgagat 39360 taaactgcag gatggcgtgc atgacaatct gtttcgtgct gccggggtta ttgtcaatcc 39420 tgacgacccg tttggtctgt gcctcgatct tgagataacc gacaacgttc gtctgattgg 39480 tacgggatat ccgaagttaa gtggtgccga tgtgccatat tatgccgata tccccgcagg 39540 aaccgggcca cgctactgga tcggcgacga atatggatgg cgaggtacgg ggctgattta 39600 ttatggtacg cagaattttg agatcggtgg ttttaaactc cagaacgtaa aaaactgggg 39660 tactgatttc gggtacggtt ctaaaaatgg ctatatccac gatatcgacc tgtggcagcc 39720 gaacaaaaac ggcgacggca tccacttcac taacggggcc agtcatatgc gcgtccgtca 39780 gattttcggc tatgcgcgcg atgactgcct agctatggtt aatagcgacg actccctggt 39840 ttacggcccg gacaaagtcc cgacaccggg gtcaattcgc cagtggatct accctacatg 39900 tccattctgg tatggttggg cgggaaatga ggccgtgggg accagtaacg acatccacga 39960 tatcgttgct acgaatatcg ggttaaccgg taacgagcag gtcagcacca ttctgaccac 40020 gcagtttaaa atctacaacg tgacaatcag cggtatcagc agcgtcaact atatgactcc 40080 aggccggggc tgggatgaag ttaatgcgat tctgaaatcg tatgcggcat ttggtgacgg 40140 ctccaggtat caggcaggaa atgtcagtaa catccgcatt aataacatca ttgagtgcgc 40200 atcaaaaaat tacagtatcg atataacgct ggaagggcgg gatatccgca tcaaccggta 40260 tatgaaactg gacacccgtg cgaaaacaaa aggcgcgctg aagatcagca gctcggcggc 40320 cccgtatgtg acaacctcta acatcgtgga ataagcagat gactatattg attcaggatt 40380 cattacgtcg cgccgttgaa gcggcctccc gcggtgcgca gactgtgctt tacacccggt 40440 cgggcgaccc gtcgtttgtg aatatcatcc ccaagtttga cgtcagcacg attgatgcct 40500 cgttggggtc tggaacgcat ccggcattta tcgttaacgg caccgaggtt agtcagattt 40560 tcgtcggcac ctaccccggc tgtattgtta acggccaact gctgtccctt ccggaccgga 40620 tacccgccac gtcggtggcc tatgatacgg gcatcggtct cgcccgggcg gccggcatcg 40680 gctggcacgc catgacaaac gcggaatggg cggcaatcgc tttgttgtgc tatgcacagg 40740 ggcaatcacc gcgcggcaat accaaccggg ggctgtcatc ggataacccc agcgagaagg 40800 ggcggcgggc agacgggctg gccgccggga ccgaatccgg aacgggtctg acgctgaccg 40860 gctccggtcc tgtcagctgg cggcacaacc gcgactatgc aggcattgca gacctggcag 40920 gcaacatttg ggagaccgtt accggggtcc gtttctgcgg tggcgagctg cagataatgg 40980 tcaataacga cgccgcgctt tacaccaccg accacacgtt atcctcaacg gcatggaaag 41040 ccgttagtgg tgtggatggg tctcttctta cgccgactgg caccggaacg ccgggaacag 41100 gttcatatgt tccaaccaca cctaactcag ttcgtatcgg cctttcgggg accgggaatt 41160 acacactgat ttatggtgaa aatacgctgt tcaccagtgc cacgaacccc ggggctacgc 41220 cggtatccga tgtcgcgcta agggtgctgc gccgactgat gttgttcccg ctgccgggtc 41280 tgatttccga cgacgcctta tcgtataaag cgggcgggga ggtcatgaca ctccgcggcg 41340 gggcgtatac caacggggct ggcgggggca tcaacgcgct actcgctaac cgtggacgta 41400 cttcagttgg tcgatctaac tctggtgtcc gtcctgttta ctacaagcct tgacattaat 41460 gcgccatacg gcgcatttct ttcctctttc ccggcgtggt gacagaagat gtttatgagg 41520 attagcttta aaaagtcgaa atggtccctc ttgttattta ttaaactgat caccgtggca 41580 gtattgacgc atttgttcgg tatcgggtgg gggcttctgg ctgtcgcggt ggtggagtct 41640 cttccatcca tcgagattaa gaggtcgatg tgaccgccgg gggtaagggg gccgccagac 41700 aaggcgcggg acccggtttt ttgttgacat caatagtgga actttccacc ggaaatgtcc 41760 agaatagtcc gaagcgatcc gctaccccga ctacaggaat attcatatga ctgaaccagt 41820 tatcaccggt accacgttga cgactgcggc tgccgtggtt ggcgccaccg gctggtgggc 41880 cggacttgac ccgggagtcg ctatcggggc tttctggggg gctatcttct ttgtcctgtc 41940 ttccaaggaa ttaacattaa ttgcgaaaac cggattcggg ggagtaagtt tctttttcgg 42000 aattatctgc gcgaattggg cggctgaatt gctaacatgg ggcgtacata agtttgcgtc 42060 aggcgccagc gatgcacccg ccgcaatggg ggccttcatt gcggccgccg tggcgatcca 42120 aaccctcatg gccatcacga cgaaagattt caccaaggcg ttgctcgacc ggttcctggc 42180 atggctgaaa agcgcgctgg tgaagactga tatcggagga ccgaaataat gtctgccttc 42240 gcattttcgg ataccatcat cacgaccttg ccggatagcc cggcattcct tttcatcacc 42300 catacattcg ctattttcaa cgttcttctc tgcctgtcta tcgtgtggcg gctgttcact 42360 ttccagcgga aaggggcgcg ccaccgttta gcaggcggcg tgatcgccat gttgctgatg 42420 gtcttttaca tgtggacacc gttccagttc gtgctgggac gcgtggccat tgtggactgg 42480 gcgaccgtcg gtattaactg catcgtcttc atcgcgatat tccgggcgcg gggaaatgtg 42540 atgcaactat tcaagtcgtg agggggcagc actatgtcgc tatcggatga cgagtaccag 42600 aaggccgcgg cgaagatcgg aatcagtgta cctgcgctgc gggcattcgc ggaagtggaa 42660 agcaatggca gcggctttat cgatggcaaa cggccaaaag ttcagtatga gccgcatgtg 42720 atgtatcagc ggctgaaaga gaacctcggg gttagcgttg ctaatggtgc gctgcggaaa 42780 tggcctgacc tggtggctac caaacccggc agctatcagt cgctgaacaa ggaagatcag 42840 gacatggacc gggcggccaa agagattgac cgcacaagcg cactggaggc cgccagctgg 42900 ggggcgtttc agattatggg ctaccactgg aagacttgcg gatacccggt gctgcaggca 42960 ttcgttaacg cgcaatactc cgaggctggg cagctggaca cactggtccg gttcctgcgt 43020 gcatcgccgg ccatcgtatc tgcggtcaaa agcaagaact ggtcgaaggc ggcgcagctg 43080 tacaatggcc cggcgtataa gaaaaacgcg tacgacgata aactggcgaa ggcatataaa 43140 aaatacgggg gtgtgtgatg cttacgccta ccgttaaaac tgtagtggcg gctatcatgg 43200 ccgccgctgt tatcttcgcc ctggtgtggc tgcataactc gctggccgag cgccactacc 43260 agcctaccat cgatagcctg aataaaacgc ttggcagcgt gaagcagcac aatgccggtc 43320 tgactgccca gctgcaggcg caaaacgctg ccatcgcgtc tatggcggta cagagcgaga 43380 aagataagca acgtatcgcc gaactggaga aagccgcgca gcggggcgct ggcgaggaat 43440 acggcagggc caatgaagtc ctgcaggaac gcaccaccgg ttccgacgtc tgccgggcgg 43500 ccagtgatgc cttcgacgcc gagctgcgga aggagcgggc aaaatgagaa agctgatcgt 43560 gaccatggtc atgctgcttg tcggctgttc cgcccgaacc gaaacgccgc cggccgtcgt 43620 ggaagtcaaa gtgccggtgc tgcagaagtg cgatatccgc cagcctgacg cgccggcgtt 43680 cgcggtggac gcattacctg tcggtgcgcc gatcgatgcc cagatgcgcg ccctgcgagc 43740 ggaacggcac caacggcagg ggtacgagat attactgcga gccgagatag acaagtgcaa 43800 aaagtaagcc cgggaaaccg ggctttttcg ttactggggt ttgcgtttac gccgctggcg 43860 catccggtat ttgaactcgt cccatcccca ctggattaag accagcatta tcgccagcgg 43920 ccaaaagata accgcgaaga accgaccgac tgactcgtcc tctgacgtta tgccggccat 43980 gagcgccata cccagaatcc agaccaccac taacatgatg tcattcagca ttctttaccc 44040 tccacgcgcc gcataacgac tttgaaaatt tcagcgtagt ggtagcgttc ggatgtaccg 44100 ttagcccagt tcaacttaat gattagacca tcaagctgtt cggtgctgtt aacgacatcg 44160 ccgctactta acacgtcgcc cgggcgcagg ttaactgcgg cgacaggggt ttcagttaat 44220 gtcgccagta cacggtcttc cagtttggag aattcatgta cggtcaaagg cccatcggta 44280 tcccacgcct tacctgcgcc cggagacatt tgcatgaaac gccggtgggt ttcttcttcg 44340 ttacggcgca ggagttcata cattccctgt agtccggtac ggtccgggag gatcagctga 44400 atcggcagac ggacgacctg gttttgctgc gcggcccggc gtaacgcgtc aaaactgcgg 44460 tatacctgga tgcccagctg gtacgcgcgg tggacttccg cctttgtgcc ggtgcttacg 44520 acgtccgcgt ttggcatggt tagcagtacg gcgtcgcaac gttccagcat ggccatcgtt 44580 ccgtccaaga aatactggtc gtcgttttgc ttcgcctgat tttcgaagtc ccgggtattg 44640 agatgcggca ccaccgggaa cagtccgaga tggccaagcg tatctaccag gtgaacggcg 44700 gtaagttcgg cgatgctgat attatgggca gtatcgacta acgcgccgca ggcgttggtg 44760 taagggcggt acggcccggc aatgtagatc agtttcattg gctttcccca ttaattcgtt 44820 tcgaacttaa ctttgtccat gtacttgtcg cggaaaggtc cattgcgcac agttcgtctt 44880 cgttgtttaa aaacagaacc cagttacgtt ccgccatttc agcagatatt tcggcgatga 44940 attcgtcggt gatctttaat cgtccggata tatcccgtag ggtattccgg gagaatttat 45000 atcggtttat ctcgcgccct ttctctgtgc cgtatgcatc cgcgttggaa attatcagat 45060 tggcaacgtg acgcgcgccc ctgaccgcca tcatttcata cctttgaagt ttttaggatg 45120 gccgatgtta ctctgaacat cgatagtaat ttcatccatg aagcagggca cgcggacccg 45180 caccagtgtt tttgcgttta ccatgtccac caggcaagtc gtttgcccgg ccactgctgc 45240 gttaacccgt tcatgccctt tcgccttcgc taactcgcta tacgccgcaa ccgtatcggc 45300 gaccatattg gccatgaagt cccactgggc ctcgtttatc ttccgctgga tgtcgtgggg 45360 gatgaccgct ttattcgctt tgaacatatt atttcctccc catggggcga tgtgagccga 45420 tccctttctg gtggccgatg tggatcttgc cgcacagttt gcagtggtag gcatccatcg 45480 gcccgctgta cccgtacgtc cgcttgatat accggatgcc tgccagagcg gccgggatgt 45540 ccggataacg ttgcttcccc tcgcatgact tccggcgcag tctgcgctta ctggccatcg 45600 ttacaggctc cagttaggca ggatgcccat ggcggccagg atggctgcga tgacgaacag 45660 cgcagacagc aggcagcaga taaatccggt gcggcggttc gtcttgtcgc cctccagcgg 45720 caacgactcg atatactctt ccgccttctt acggcctgcc tcccagcgcc agtatgcccg 45780 gcatttcgcc ccggtaccgt tagttgggtc gctgtacggg ttgctttttt cggtggcgcc 45840 ctgcaggccc gccagcacac cttctgcttc ttccagagta cgggccggga tgaattcatg 45900 cgcgccgggt accggtactt cgtagccttt ctcgctttct ttgatcatgg gttaaccctc 45960 gtagttcatg ttaaaggtga tgcgtattac tgacttaata cccaggtgat cggtaatcgc 46020 caggtaattt ggtggctcgc tcatcatggc gaattctttt accgccatat acccgggact 46080 taacggtctc cccctggctt tcatcccggt ttcataggcg gagacgaacg ctttggcgct 46140 gacgacctta cggtccagca caaatcccca ttccatgagc aaggggtaac gcggtggtgc 46200 agttttggcc gttggcttat cagcgaatct acggctgctg cgataaatgc cctgcgggat 46260 ggggtacacc cgacaaaccc cgtgatagcg ccccagttct tccagcccat agaaggtgtt 46320 gcagcggata tcgtattcgc gttcgccgtc cattaatgcg gcaactgcgg ctttcagttc 46380 gtagtaatac tggaaccact ggtggtggcg gttgaccacg cccgaaatga tctgctggtc 46440 aatccggtga acaatctggc tcataatgaa aaactcccgt cgttgccttc gggagtaata 46500 ttagttgcac acgaatcgta tgtcaaacag ttttttaagt tattcaggtt caggttttag 46560 ccgcgggaat ctttccagcc agccgtgatc gataatcacc atatacgcct ggcggtaggc 46620 atcccgtatg gcagtgtgtt gcgctaacgg gcagcgcgct tccgcctgtg cgtcagcgag 46680 ttcccacagg ccgccttctc ccggacggag acggtcccac cgcttcatta gcgtgcgggt 46740 atcgttctca tcccgaaagt cccacggacc ttttccctct ccgccaaaca gcccgttttc 46800 cagttggata atatccacgc gtggtgcatg cccccaaacc tgcgggcgga attcttccca 46860 tgcttgatag aggcccatgt aacccagttc atcctgaccc ggggagcaca tgtattcttt 46920 aagcgcctgg tgtacccagc tcatgaaggt gatacgagcg tcatcgatcg aaaccggttc 46980 agcatcttcc ttcgcgaaaa acgcttccat tgcggcttcc gggttttgca tcgcctgact 47040 gacccaccac ttaaccgttt cagggtcaat gtcgccccgg cggcgacgac cggcaccctt 47100 ggctaacgta acgctgaact cgcggaacca gccttcgtcc gcgtggaaca tgacgcacgc 47160 gaatgacaga aggtagccgt cggtcttgca tgacaggttt tccacgtcga atacgaggtg 47220 gattttgccg atgtgttctg gttttgctct cataggtgtt cctcttcttt ggtccattct 47280 ccgctgccgt cggcgcgggt cactttaata atttcgtctt tttccacgtg catcaccggc 47340 agcggtggaa atgctacggt accgtcggtg tggcataccc gcacttccac ccgccagggc 47400 ttccagaaaa cgggtatcca gtcgcaatgc tcaatcacga tgccggagta ttcccggcca 47460 ttgcatttat cccggaagcg gaccatgtcc ccgtagagcg ggtaatcagg gtccggcggg 47520 agggcggcat atttatccgc aattgatctg caaacgtcat acattgacat attaatcccc 47580 cataaaaggt tcgcagctcg ccgcgcaacc ttcgtaatct tccggagcgt cttcacgaac 47640 cggcactgtc aggtcgaaac tggcgatcag ctgctgcgta tttcggtatc cccggaagaa 47700 gacccgtggg tcgtctacct ttaccccttt gaccatgttg tcgccaacgc ggccatagcg 47760 ttcttccatc tcccgcgtcc actcgaagaa gtccagcacg tccagcttgt cagtcgggaa 47820 ccagtcgatc agcgggtaca cgcggacctg gcccgtctga cggctaaccg tggtcttctt 47880 acgctgcagt tcgtccgtac gaatgccgat cgccgtctgg taggtgccgc gcttccagcc 47940 gatggaccgc atgtacgagt ggatcacgtt ctccttcaat tcccgggtgc aatggatgta 48000 gtttttgttc gggatgccgt actttttgag catctcttcg aacaccctgc cttcccggtc 48060 cgccgtctcg tacgagatga cccgatgggt acagccgcgc tttttgccgt ggtgaacaac 48120 cgcttccagc cataccgtgt tgaagccgaa gtgctggtcg cagtctcgta cgaagtccag 48180 cgtttccgga ttctcacggc cggtattggc gaagcacacg ataatctcgt acttatcggc 48240 gtactctttc aggatccggt aggtcatgta agcggaggtg cgccccccgc tgaacagcac 48300 cagtaagcgc ggctttgcca ttagaaatcc ccgtctaact cgcccaggtc atcggcacgg 48360 ccatacagct cttcgaacag gatcatcgct gcggcgtaca ccagcgtccc gcgaagttcg 48420 ttgatccggg cctgtttagt cggcagcgtg cgggcctcaa tggttttctt gataacctgc 48 480 tgcgccaggc cggcgtcgct gtccagcata tgcgccatgg tcagaatcgg ctgttcgata 48540 aacggcaggt cattggcgtg acgctcacgg cctttaccgt acgccgcctg ttccagcgcg 48600 ccgaggaagg tgcgcagcag cggcaggtag tcatcacggt ctttctcgtt tttgaaccgg 48660 aacaaggtcg accggatgcc ggaatcatcg gcgaccatag tcaggtccag gtcgtcatta 48720 gtatccgtgg ttgatgggcg taactccgga gcgaactttt catactctat gccctggcaa 48780 tcctctgctg ccttatcgta cgcagaagcc aggccactcc atttcagttc ttcaaccgca 48840 cctactggca gtgtcacgtg aggccatttt gcaccagcct taatcttgat gcgttgttcc 48900 ggaaacaggt ccggagcggc ttcgtttttg atagtcacgg tatttttagc atgagtgttt 48960 ctacccgcat cggcggactg gcgggcttcc ggttccactg gccggggggc gacgagcgta 49020 tcgatcgctg acaggatgct ttcgtctgac gattcgaaat caagttttaa cgtcgctgca 49080 atcgtttcca aggttgtttg gtgttcaaac gcctgcgcat tcacagcgcc taccatggcc 49140 agcatttcgt cccagctgcg gcctgtaaca cccagcgcgt tcgccagctg gtcacgcatt 49200 tgcgaatcaa tgctgaccgg ttcgtcaatg gacgggttac gcagcgaaag gagtttatgc 49260 ccgttgagat gcgcgaacat gagatagttc atcgcgtcga tcaacttacc cttggccagc 49320 gaatcgcgaa tgcaggtacg gcattcatgc tcggtcagtt ctttccatgg ttcagcggtc 49380 gcccagcctt tgcgcttatc cgcgccgtag taaagacgac caagcatctc atcgaagacg 49440 cctttaactg aggtcaggaa cgcttcattc aataaattgc tatggaaggg cggccagcgg 49500 agttcggttc tcgggtgaac gattctgttt ttggccggca tttctttatt ctctgacatg 49560 gtatatctcc gggttgtttt gttgttcgat tagaatacta gctgcacacg ttttgtgtgt 49620 caaacgtttt ctagaaaatc tacagttccc accataaagt ttcggatgaa ctgggcgccg 49680 acttgaggga cgattgcatt gccgtatccg cgcagtcgca ccactcgggc gggtacccca 49740 ttagccaacg ggaaaacgcc ggatccaacg ggcctgaact tcccatcccg gcatagcagc 49800 cagtcagcat ttgaccacgg gccgtgatcc tgatcgggaa gtcgggggca ggcgtacact 49860 tctccatgcc cttccggtag ctccccgata gctgccccct cgatgccggc gagtccggta 49920 ctgtcagcgg tgtcgggtag ctggcgagac gaaccgcgcc gcccagggtc gtcgaccgat 49980 ccggatggcc cgctgcgccc gcctccccgc gtacctgatt gttgtcgatc gtcgtcaccg 50040 ttggccaggt cgccagctgc gccgccacgt ccagccggtc gacggatagt ttgccattcc 50 100 ttatccgccc acccgcgtag ccgcctttcc agtccgtcgc tgacgaggtc ggccaggtcg 50160 atagcgccaa agaaaaggcg atctctttta tgcggggcgc cgacgctgca cgctggcaat 50220 actgccgacc cgcaggcgta accttcttct tccagctcaa cgaatagagc atcgagccac 50280 aattctttaa ttgctgcgct aacctgttcg ccaaaaataa ctggaggtcg cagctctgcg 50340 atgaggtcga gaaaggccgg agccaggtga cgggagtcgt cccgcccgcc tcgttttcca 50400 gccacactaa aaggctggca cggcggactt cccgtacaca ctggcgcata cgccggccat 50460 ccggcgagtt taagggccag cggccatccc ccgataccgg cgaagaagtg ccactgacgg 50520 aaaccccgga ggtcttccgg ggcgacttcg gtgattgatc gttcatcgac aattccatct 50580 ggcaggtggc cgcgcctgat tagttcacga agccacgctg cggttttagc gtcccactcg 50640 ttgtagtagt ggaacggttt agagccgttt atgtatgcca ttctgcgcct tcttctcttc 50700 gcgtcttttg accgcacaat cggcatggat cgtagtccac gttccggacg cagacctttc 50760 aagatacccg gcgccggccg gcactggctt tttgcagtag caacacatag ccacgtattt 50820 atttctggcc atctttgacc ctcgcgaaac aggcatacgg gccatcgaat tccgtcggcg 50880 ccgtatacag gagaaaccag ccggacccgt taagcgacgt cgggcgcggc atccaggtac 50940 gcagcacaga ggcgcgcatc tcgtccgtct tcgcgttgtc gtacgccacc cgcagcggca 51000 cttccagcgc tcgcggatag ccttcgccca ggtagaatcc ctcgcactcc aggttgtatg 51060 catccagcag cgcgtcgaga ttggacccat catagttatt actggcgtgg aagaagacgg 51120 gatggtagta ccaggcgtcc gggtcatacc cgtccgccag gcttacctgc tcgccaatta 51180 cgccatcgtt atacacgttt ggctttggca ttcttccctt cctcttcggc aactgaccag 51240 acgacctcgg tgaacgggtc agggttgatc gtcttcccga ccttattctg gtcgaggtac 51300 cagtcgtcgc cgcaccacag tttgacgccg tgggcatccc ggcggacttc aacgtcgaac 51360 gttttcactt cggtgatctt gccgttacgg gttacagttt tggttaattt catggtcttg 51420 gcctcacgtt tatgaacacg aacctgtttc atgggtcatt ccccgaggta attcatggcg 51480 ccgcaatccc ggcatacaac ttcacgcggt ttcccttccc acgtccattc cgtcacatcg 51540 cattgatagt gactacagct atcctgaatg cgctgcgttt cctgccgttg cgcttcgtat 51600 ttagcgtcct gctcggcgcg gcgttcatcc cgtaaacgct gcttgcgttg ttttgatgat 51660 tcgaatgtca ttgctatacc tcgtcccact gggcgatcca cttctcgcgg acgtcctgca 51720 tgatgttggc catgggcagt ccgatgtcca tgagcgcttc ccgggagatg tactccgggg 51780 catgtttttc ttcgtcttcc ggatcgaaga tgactatcgc ggcgccgaag cccgcggacg 51840 ttgcacctgc ggcgcccgtc ttcgctttga accataccgg cggttcgaaa ccgatacgcc 51900 ctttgatgaa tatggtgcgc gtggcgatgg tatctggcca ccatgtttca gcggtagccg 51960 ctttgatcac ccagaccgta cccgcgcctt tcttccgttc ctcttccgcc ttggccatga 52020 tgttgaccat gccggtcagc ggcacttcca cagcacggtt acggctgtat ggcgggttgc 52080 cgaaacccca tacccgccga acgtggtcgg cgacatcgta cacttccgcc tcggcctcca 52140 gttccgcctg tatccttttc agccggcccg cccagtcctg gcgcagcgcg ttgtcctcgg 52200 cggtgtaata gcgcgtgcat ttggcgttct ggccatcggt gaacaggtcg agcaccagcg 52260 ggccgaacag cttgtccagc gcgaagaaca gccagtcggg tgttcgccac tggtcgccta 52320 tctctttcag gtcatgcgct tcccgggctt tcagcgcgat gaggttgtca acgtattcac 52380 tcacaaatta gcctccatgt atggacttgg tcgccctggg tgatgagatt cacaatgata 52440 aagccgcctt ctttttccat tcgcgcttta tccgcgaatg ccggaattgc ggcaaggaag 52500 tctttccatg gcagggggtt aaacgcgcca atggctaccg agatttccag gtttttattc 52560 ccaccggcct tgtgggaaac gcagcaaagg ctggttccgg ttttatcccg cagccaacgg 52620 tctacgctcc ggaggaattt cccgtctccg gcggttaaaa tgtcgcactg gacaacgata 52680 tttgtcacgt cactcatggc cttttctccg ctaaaaattc gcgtaatacc ttttccatgg 52740 ccaattcgtt tgccgcagcg ccaggccatt taccgagaag ccgcgcatta ttcggtacgg 52800 tctgcatttc cacaagacag actttgttac ccaactcatt gcgagaatgg ttgatactca 52860 ggctgtaaat gctgacgtcg tccgggccat cccataggtc ttttcggata ttaagatatg 52920 cctgaatatt acctgcatcc gggatcgcac ctgcgctcat aatatctacg cacatttcct 52980 ggatgacctt ttggtcgtta attacgtttt tcatttccgt ttttccttct gtcgtgacac 53040 gaactggact ggggtgacga cctcaccgaa attcgggtaa cggctgcgca ccagctcaag 53100 ggtcagcggg ttgatctccg cacgcggcgt cttcacgtcg tacgcgcggt ccgggatgtc 53160 gatgcggcgc atgtacgtcg gtcgcatccc gacgcgtacg gcgtagttat acgcttcctt 53220 cgggccgttc gcccagacca cgaagccgac cccgcggcgc tgcagataat atgcctgcgc 53280 cgtattggag tcatcgcgag gcagattttg tggtatcgcg ggaaaacggg cgctacttcc 53340 tttcacggtt cctgtatacc aattggtcga agcatggcgt tcttccgaac actccggcgg 53400 gtacgggtca ttgatatccc acgtctttcc gcaccaggaa cagaacacct ggtccgattg 53460 ctggatagcg tttttgtggc cgttagtttc catcggtgtc ctccatcatc caggacggcc 53520 atacgccatc gcggatcatc tggcgctggg ccttccagtc ggcctgcgcg agttctttaa 53580 ctcgggtccg gatgacagcg tcgggcataa acgccgtcat tactttcgtc aggaaaactt 53640 tgttgtaggg gtcctccacg cggcagttta acgcccgggc gcaggactgg atcgccgcct 53700 tatcattgcc gtgttctttc atgcacagca tgagcgtaac gatcatgtct atcgcctcgg 53760 cgatatcccg gcacgctttc ttttctggcc cgtggacctc aatggaaata ctggtcgccg 53820 ggaataacag gtggtctttg tacgggcgca gccagtccgc tttcgcccgg tcttctgcgc 53880 tggtggtcat acttcgatgt cctcttcccg gatcagctgc agggcgttgc cgttcactgc 53940 ccacggttgc cacacgtcca ccaccagcgc cgcacggaat gaccggttga agcagttctc 54000 gatcatcgcc cagttatcgt ccggacggtc tgacgcaatg ccattgcgtt cccagtgcca 54060 ctggcgaggc gcctgggcca gctcgcggag gggcgggcgg gggtgtgagt agggattgca 54120 caggccggaa cgcagcaggc cacgctggag ccatgagcgc tgccaccaga ggtcacagcg 54180 ggtcgacccg acggcgtatt cctcttccag catgccgcac atgatcagcg cgcacacagt 54240 atcgcgtggc gccggcgcac cgatgaggtc gaaatcctcc agcctcttcg ccaggcggtc 54300 ggcggaccct tcgtcctgcc cgttgccgtc ggtacggtca tgcagaatta catcgaggat 54360 gatggccgga aaaacgactt gtttgccgtt gcgggtaaag cgggggtccg gctcattgaa 54420 gagggcgtga tacagccgcc cgaaccactc cgacaggtca ggcacgaagt cggcgatatc 54480 cggccagctg cgttcctctg tgttgtggat gcgcacggac gtctcttcct ctatcgggtc 54540 gtactcgacg cggacgatgc agcgcgggcc gtgcgggagg ggaaaaatgt agatggtctg 54600 tttgccgatt cgattctggt caaagcggcc aaacgacatt agatgcttct tcatgggatg 54660 ttcctttttg tggactccca agaaatgtag ctgaacacga ttcgtgtgtc aaacgctttc 54720 tgcaggcaaa aaagaagccc ggacaaagcg tgccgggctt taatgtcagt ggaacaccga 54780 gcatgaagat ttcatcccat gtcccgatca ctatacgtca ggattgcgat aaatcaaatc 54840 ccagtaggtg aatgtttcca ggtcgacttc cgtccagtcc gggtcgtcca ggtacgacag 54900 gcaggtgccg gcatcctcgg cgcagacctg cccggcggcc gcattatgca gcaggcggac 54960 ttcccggaaa tagatgaacc actcgcggca tggcgtatag gactcgggct gacgggtctt 55020 gatgatctgg cccgtctttt tgtcctgcca gtacgccgtc cgtttcttcg ccaggtagcc 55080 catatcagcc caccctcatg acgcgggatc ccatgcggcc gtaaatcggg tcgcgcagca 55140 cccagcggat agccagctta taccccaact ggtaccccag gcgccgcacg tagcccaggt 55200 ccgcaggccg cttgccgctc acgaagaagg actcgccgac agccatagcg ccaagcaggc 55260 gtttatgctc ggcgatatgg gggttcggtt tagcgtgttt acggcctgcc atgtcacacc 55320 tcgtcgtcgt cttccagctg cgcgtcgacc tcaaccgtga tgtccatctt atcgcggaag 55380 acgtcaatga cgtcctgcag cgacagcacc gtctggaaca ggttggccat gtaggtcagg 55440 aacgtaccgc tgtcattgtt gtagcgctcc agcgtggctt cgtagttggc gtcaacatcc 55500 gcctcgccga tgtggatccc ggagatgatc gccttgtcgg taaggcggaa gaacacgttg 55560 cccacgcccg ggcgcatctc gccttcgtcg attcgcatgt tcagcgcccg aaccgtgtaa 55620 tgccgcgcca ggtagtcgag gaccacttcg tccttgtgga tgtcaatgtc cttgaacttc 55680 acgtcatcgc catcgtcgtg cttgatgtgg atgaagtcct cgccggtgac accctcgatg 55740 tcgccgcgta cgaccttctc cattgactga cgcagcacga agtcattgat cagcaggtgt 55800 tccactggcc aggtaccgaa cgcggcacgc agtagggagt taatctcttc ggcggtcctg 55860 gcgctggtgg tgaacacgta gacgtacggg acggcgatga tcacgttgta gcgggtcggg 55920 cggataggcg cggttttcag catttcggct tcaacatcgt ctttcagctg cgcccagtct 55980 ttccgggtcg gctcccagcc ttcaatctct ttctcgcgcc aggtgtccat acgcttcgtc 56040 acttcgttgc gcacgctgac gccgggcagc acgcgttcac gcttttcggc ctgcagcacg 56100 atggcgttag tacccgggat gcccatggca aacttgccgc ccacgtagtc cgcgtacggc 56160 gcaaagccaa tcgtcttata gccgatcggg tctttcactt catgcttcgc cagcagatcg 56220 ctcacacggc cggcggcgaa ttcatggacc gacatttcgt ccatgttcgg cgtgttcagc 56280 agcgtgcggt ggaaactttt taccgacttc tcgccagcgt ttgcggcgcc aaagagcgcg 56340 ccgagatgca gaatgatgac tttctcaaag cctttaactt tcattggggg tatctccgtt 56400 tgcaaacaga ttcaggaatg gcgcacgcac aagggcggcg gttagatggg ccagcagcac 56460 acggttcgtc tcccgggcgc tacgcaggtc tgccgccatt tcggcatact ctttatcgac 56520 tttgacaaag gcaccttcgt cagcgtcagg gtcgaccatc gtgttgccga ggacttcggt 56580 atacacccgg gtcgcttcat cctcgatgtc ggcgataatg ctgttcagga tggcgatctt 56640 actgcgtacc tggtcgagcc ggtcagcgcg ggtcgtcgcg tacgctttca gcagttcagt 56700 gttcatccgc gtgctctctt ttcgttacgg cggcgctggc gctcatcctt gcgcttctcc 56760 acctgtgcat tccagcggtc gcgttcctct gactccgccc ggttcttgag ccagagttcc 56820 tcccgttcgc caagcgcttt actgaccgca ccgtcaataa cttccgtggc ccggaccagc 56880 tcgtcttccg tcatttcagc ggcagagcac ttcccgatct ccgtctgcag caaacggaca 56940 acggcagaga tgccgatcgc gtcgatggcg atacgggcct tttgcgcata cagcagtctt 57000 tggttaaccg gcatcatttc acccccgttg tcaggacgac atagaggacc gccacgcagg 57060 cgaccagctc gatcagcacc atgaacagga tggacgccag cagcagtttc gcaaatgacg 57120 gcaggtatgg agtaaggcgt atgcgagcat gaccgtccag ctctttgtgc ttcattggtc 57180 ggcggttacg tttggtccag cggcgtatcc agttttcgcc gcggcggtgt acgaggctat 57240 cattcatcac ggttccctcg catggcatcg cgcaggtctt tcggcgggta gattttattg 57300 acgccatcac cttcacgcag gaaacggatt aacatggcca gggtctgcac gatctcttct 57360 tcgacatgga cccaggtatc acggcgctcc gcgtaatgca ctgctgcctt gatcacctcg 57420 ccggcctctt ccgagaattt cagcatggtg taattcggct gcgggtattt ttcgatagcc 57480 cgggccgatt cggctcgtgc ctggtcgacg aggatatcga aataatcggc cttcgcttcc 57540 gcctgcgaat tcatctgcag gtaaaagatg gccagcgtcg tgaggaattc cgggctggcg 57600 aaagtgatgt ccccacggcg taccgcatcg cgataccggg cgacgctttc cgggttgact 57660 tctctgaact cattttcatt tgacatgggg tttccttctt agtgtttttc gccagcaatc 57720 tccgccagta cggcagcgac ttccggcgtt ggcatgtggg tgttagccca gtacagcagc 57780 ccgatgatgt agtggatcat ctgaccgacc tctgccgcgc cgcgggcttt tccgcctttg 57840 gctttcgcat aatcgccttc gctgaacagc actttgccgg taccgcggta gccaacaatg 57900 gccgaaccgg tatgcgtgac gtaaatggcc acggcgtatt tgtcttccag ggatcgaaac 57960 gccgggccag cgtcgagtcg tttgcgcggc gccgcaacgc ggttcaccgc cagcgcgaca 58020 ttactcggtg tcgggttttc cattgagcgg ctctccgttc agggtgtaga tgacgacgcc 58080 cggcacgctg acgtcgatcg acagcgatgg cacaaagccg gacatgacgt tctgcggggt 58140 gatggtggcg cgtttcaggc cgttctcgta catgatgttc gcgatgcctg ccatgacgga 58200 cttctccacg atgttctggt tcgtctcttc gcgcatggtc agcagctgtt tcaactcttc 58260 gacttcattt ggaatgtcaa aggtatgctg taacatccgg ataagcgtaa tggcatcatc 58320 acgggtgatc ggggtcagta gctgggcata agcagggtca atatggtcga tcatgatctc 58380 gccatcctgc tgtcctggct tacggtaggt atgcaggact cgcgctaact cagggtagcc 58440 gggcataatt tccgacgttt tcctttggtc atcatatgac atagggtgtc tccgggtgaa 58500 aagggtggta cggcaaaaaa gaggtgccgc gtcctacagg attaaacttc gtcgtcttcc 58560 ggtgtgccgg cgccgtcatc aacgcgcttg atcgccacct ggataaacgc acggcccgac 58620 gggtacatga ccagcgccgt ttccagtgag aactgactat tgcaggcccg tttggcgtta 58680 cgcagggaag acgacacgcc gttacgcatt ttgtagcgca gcgccgtggc ttcggtctgc 58740 aggtctgcca gcgccttgct gctgtccagc tcctgcgcat aaacgtagac ctcgcccggc 58800 ttgaggccga tcaggttgcc agtgatactg ttagcccgga tacctgacgg cagttccacg 58860 tccgtctcca tggtcatcat ggccggcgtc aggtcatcca ggataatcgc gtcgttcatc 58920 ggtattctcc gtcgttaaat ttgcgtatct gtcacgctga aagatagttg catacgttcc 58980 gtgtgtcaat cgttttcact gcagcttttt caagtaagaa atttcagccg gctaactttt 59040 tgaagtaaga cccgaaccgc tatggcgccg gccatggtta ttacggg 59087 <210> 2 <211> 585 <212> DNA <213> Unknown <220> <223> Klebsiella pneumoniae bacteriophage YMC15 / 09 / U2874_KPN_BP ORF49 <400> 2 atgtcgctat cggatgacga gtaccagaag gccgcggcga agatcggaat cagtgtacct 60 gcgctgcggg cattcgcgga agtggaaagc aatggcagcg gctttatcga tggcaaacgg 120 ccaaaagttc agtatgagcc gcatgtgatg tatcagcggc tgaaagagaa cctcggggtt 180 agcgttgcta atggtgcgct gcggaaatgg cctgacctgg tggctaccaa acccggcagc 240 tatcagtcgc tgaacaagga agatcaggac atggaccggg cggccaaaga gattgaccgc 300 acaagcgcac tggaggccgc cagctggggg gcgtttcaga ttatgggcta ccactggaag 360 acttgcggat acccggtgct gcaggcattc gttaacgcgc aatactccga ggctgggcag 420 ctggacacac tggtccggtt cctgcgtgca tcgccggcca tcgtatctgc ggtcaaaagc 480 aagaactggt cgaaggcggc gcagctgtac aatggcccgg cgtataagaa aaacgcgtac 540 gacgataaac tggcgaaggc atataaaaaa tacgggggtg tgtga 585

Claims (15)

카바페넴(Carbapenem) 내성 클렙시엘라 뉴모니아(Klebsiella pneumoniae)에 대하여 특이적인 세포 사멸능을 갖고,
서열번호 1로 표시되는 유전체로 이루어지며,
명칭은 YMC15/09/U2874_KPN_BP이고, 기탁번호는 [KCTC18571P]인 박테리오파지.
Carbapenem-resistant Klebsiella pneumoniae has a specific cell killing ability,
Consists of the genome represented by SEQ ID NO: 1,
Bacteriophage named YMC15 / 09 / U2874_KPN_BP and accession number [KCTC18571P].
삭제delete 제 1항에 있어서,
상기 박테리오파지는 시포비리데(Siphoviridae)에 속하며, 전체 게놈 크기가 59087bp인, 박테리오파지.
The method of claim 1,
The bacteriophage belongs to Siphoviridae, and the total genome size is 59087bp, bacteriophage.
삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 제 1항 또는 제 3항의 박테리오파지를 유효성분으로 포함하는 항생제.An antibiotic comprising the bacteriophage of claim 1 or 3 as an active ingredient. 제 1항 또는 제 3항의 박테리오파지를 유효성분으로 포함하는 소독제.A disinfectant comprising the bacteriophage of claim 1 or 3 as an active ingredient.
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