Patent Publication Number: US-2019175670-A1

Title: Postbiotic-based composition for treatment of ocular inflammation

Description:
FIELD OF THE INVENTION 
     The invention refers to a composition comprising a fermented product of  Lactobacillus casei  or  paracasei  species, preferably for use in the treatment of eye inflammation syndromes and to a method for obtaining the same. 
     The invention relates to the use of the supernatant of  Lactobacillus Paracasei  in the treatment of conjunctivitis, in particular of Vernal keratoconjunctivitis (VKC). 
     BACKGROUND OF THE INVENTION 
     Conjunctivitis 
     Conjunctivitis is an inflammation or infection of the eye conjunctiva. It is characterized by conjunctival vessel dilatation, leading to hyperemia and edema of the conjunctiva, usually manifesting with associated discharge (Leibowitz H M,  The red eye , N. Engl. J. Med., 2000; 343(5):345-351). 
     Conjunctivitis can differ based on the aetiology. It can be related to viral or bacterial infections, or it can be allergic. Allergic conjunctivitis is by far the most common one throughout the population and it occurs between spring and summer. Viral conjunctivitis is the most common infectious conjunctivitis and occurs primarily in the summer, while bacterial conjunctivitis is most frequent in children and is observed from December through April. 
     Conjunctivitis can be primary or secondary to a systemic disease. In the first case, topical treatment is to be preferred, while in the second case systemic treatment should be sought. Treatment depends on the cause of the disease and is carried out with antibiotic-based eyedrops, prescribed for bacterial conjunctivitis; anti-histamines, anti-inflammatroy or steroid eyedrops for the treatment of allergic conjunctivitis and no cure is available for non-herpes viral conjunctivitis (JAMA, 2013; 310(16):1721-1729, doi:10.1001/jama.2013.280318). 
     Vernal Keratoconjunctivitis (VKC) 
     Vernal keratoconjunctivitis (VKC) is a chronic, bilateral inflammation of the conjunctiva. VKC affects in particular young children (especially boys) from the age of 4 to 20. The incidence of the disease is 1-10 cases in 10.000 individuals, but it has been rising in the last decades. The exact aetiology of the disease is unknown but VKC is present mostly in allergic individuals (with asthma, atopic dermatitis, allergic rhinitis, etc.) and includes eosinophils and mast cell hyperactivity. The pathophysiological feature is a dense mixed cellular infiltrate with sometimes an extremely thickened epithelium. It shows pronounced capillary proliferation, fibrosis and a thickened extracellular matrix. 
     The clinical picture is characterised by pronounced subjective symptoms and the emergence of giant papillae, mostly on the upper tarsal conjunctiva. Distinction can be made between a limbal form and a palpebral form. Corneal changes are the most threatening complications with development of corneal erosions and shield ulcers. It is a debilitating disease characterized by burning and itching as well as photophobia. Current therapeutic options are aimed to prevent long-term tissue damage caused by chronic inflammation and depend on the severity of the disease. Mild cases are treated with anti-histamines and mast cell stabilizers. Severe cases are treated with steroids either local or systemic and with cyclosporine under strict medical control. Due to the limited clinical benefit and the adverse side effects of these immunosuppressive drugs, especially in the eye where they may cause increased intraocular pressure, cataract formation and glaucoma, these drugs are far from ideal, and a considerable effort is needed to identify alternatives. 
     Therefore, there is a need for new drugs or compounds capable of either preventing or treating conjunctivitis without causing side effects. 
     Allergy, Microbiota and Dysbiosis 
     The microbiota is the community of commensal bacteria inhabiting our body (Yatsunenko et al., 2012). It is emerging that we are made of ten times more microbial than mammalian cells which contribute to a hundred times more genes. Hence, the microbiota provides a set of new functions that over the years our organism has learned to exploit (Qin et al., 2010). This enormously enhances the genetic variation among individuals that is provided by the human genome (Li et al., 2008; Mueller et al., 2006; Qin et al., 2010). One important function of the microbiota is the maturation of the immune system and protection against some infectious agents (Hooper et al., 2012; Khoruts et al., 2010; Reid et al., 2011; Swiatczak et al., 2011). It is becoming clear that especially in the early phases of life the microbiota ‘educates’ our immune system to deal with both innocuous and harmful bacteria and to establish a balance among the two that is characteristic of a healthy gut. Indeed, the microbiota is composed by symbiotic innocuous bacteria and potential pathogens also called pathobionts (Chow et al., 2011). 
     Recently, it has been shown that several disorders, including allergic rhinitis and atopic dermatitis are associated with a disrupted microbiota, also called dysbiosis (Robles Alonso and Guarner, 2013). An altered microbial community may trigger allergic reactions characterized by an increase in Th2 type of responses, IgEs, eosinophilia or basophilia and mast cell activation (Cahenzli et al., 2013) (Hill et al., 2012). Also the eye mucosa is colonized by the microbiota and it is likely that dysbiosis may be responsible for some allergic manifestations or for susceptibility to viral or bacterial infections leading to conjunctivitis. 
     Probiotics 
     Probiotics are defined as live microorganisms that exert beneficial effects for the host when administered in adequate amounts. However, the administration of probiotics should not be arbitrary as each strain may produce specific metabolites in the fermented product with distinctive immunomodulatory properties (Klaenhammer et al., 2012). For instance, when the activity of several Lactobacilli on the immune system was compared, it was found that each strain has very specific characteristics (Mileti et al., 2009; Tsilingiri et al., 2012; Tsilingiri and Rescigno, 2013). It was thus found that  Lactobacillus Plantarum  NCIMB8826 has detrimental effects due to its immunostimulatory properties in mice and on healthy human intestinal tissue (Mileti et al., 2009; Tsilingiri et al., 2012), while  Lactobacillus rhamnousus  GG and L.  Paracasei  B21060 can be detrimental only on inflamed tissues like those of patients with inflammatory bowel diseases (Tsilingiri et al., 2012). 
     By contrast, the inventors found that metabolic products of probiotics—that were called postbiotics (Tsilingiri and Rescigno, 2013)—are very safe also on inflamed tissues, presumably because postbiotics lack the microbe associated molecular patterns that may further activate inflamed tissues (Tsilingiri et al., 2012). The use of probiotics ( L. acidophilus ) in eyedrops has already been proposed by Bonini et al. and has shown some efficacy in controlling symptoms of VKC in 6 out of 7 patients (Iovieno et al., 2008). In this clinical trial, patients were treated with probiotic eyedrops for 4 weeks, while signs and symptoms of VKC were being recorded. While symptoms were improved both after 2 and 4 weeks, the improvement of clinical signs was evident after 4 weeks. Prolonged use of probiotic-based eyedrops has not been tested, but it cannot be excluded that it might lead to a permanent change in the eye microbiota composition, or on the community of commensal bacteria inhabiting the human body (Yatsunenko et al., 2012), with unpredictable long-term effects on the eye immune homeostasis. 
     The Supernatant of  Lactobacillus paracasei    
     The putative therapeutic use of strains of  Lactobacillus paracasei  strain CNCM I-1390 (Budapest Treaty deposit), redeposited on Jul. 26, 2017 according to Budapest Treaty with CNCM (Collection Nationale de Cultures de Microorganismes, Institut Pasteur, Paris FR) rno. I-5220 (hereinafter also named as B21060), in particular of the fermentation supernatant thereof as an anti-inflammatory in intestinal diseases, is described in WO 2011/009848 A2. 
     DESCRIPTION OF THE INVENTION 
     The present invention relates to the use of a fermented product of  Lactobacillus  species (postbiotic) for the generation of an eyedrop formulation to protect the eye mucosa from infections and allergic reactions and subsequent conjunctivitis. 
     The advantage of the postbiotic is multiple. First, there is no introduction of live bacteria that are normally colonizing other mucosal sites in the eye. Second, there are no microbial associated molecular patterns (MAMPs) normally associated with the bacterial cell wall such as endotoxins (LPS) or lypoteichoic acid (LTA), that may be potentially harmful. Third, a postbiotic has anti-inflammatory, Th1/Tregulatory cell skewing and barrier-protective properties on epithelial cells, including corneal epithelial cells. Hence, the use according to the invention of a post-biotic eye-drop is safer and probably more effective than a probiotic eyedrop, with the advantage of not affecting the composition of the eye microbiota by introducing species that are not normally present in the eye. 
     The invention refers to the use of a fermented product that can re-establish the homeostasis of the eye mucosa and protect it from both types of reaction. The fermented product is obtained at a non-canonical temperature of fermentation. The fermented product can on one side skew the T cell response towards a Th1 type of response that can be protective against pathogens and can counteract the pro-allergic Th2 type of response initiated during allergy. On the other hand, the fermented product does not favour the induction of an acute inflammatory response. The fermented product of the invention has immunomodulation activity both on the cells of the Immune system and on epithelial cells and promotes the formation of the epithelial barrier thus protecting the mucosa from external agents and is therefore particularly suitable for the treatment of conjunctivitis, particularly of VKC. 
     The fermented product can be obtained through the fermentation of different substrates, such as for example sodium lactate. 
     The invention refers to a composition comprising a fermented product of  Lactobacillus casei  or  paracasei  species, said species being characterized by comprising in their DNA genome DNA sequences essentially identical to SEQ ID No 1 to 5 sequences, proper diluents and/or eccipients. The fermented product of the invention is produced by the method as below disclosed. 
     In a preferred embodiment the  Lactobacillus  species is  Lactobacillus paracasei , preferably a strain characterized by comprising in its DNA genome DNA sequences essentially identical to SEQ ID No 6 to 18 sequences, more preferably the strain deposited according to Budapest Treaty with no. CNCM I-5220. 
     Preferred uses of the composition of the invention include use in the treatment of eye inflammation syndromes, preferably of conjunctivitis, in particular of Vernal Keratoconjunctivitis (VKC), in human and veterinary medicine. 
     It is within the object of the invention a composition further comprising adjuvants, and/or other therapeutic agents known to the skilled person for ocular inflammation syndromes. 
     Preferably the composition of the invention is in the form of an eye-drop formulation. 
     Preferably the composition of the invention comprises the fermented product as above defined at 2-40% volume, preferably 10-25% vol, more preferably 25% vol. 
     It is within the scope of the invention a method for obtaining the fermented product as above defined characterized by: 
     a) growing an inoculum of  Lactobacillus  strain as above defined in a suitable culture medium, at a temperature ranging from 4 to 40° C., preferably at about 37° C., to have a biomass and allowing fermentation of said biomass at a temperature ranging from 4 to 40° C., to proceed for 12 to 36 hours, preferably for about 24 hours, to get a fermented biomass, and 
     b) centrifuging said fermented biomass to get a pellet fermented biomass and first fermented product; 
     c) incubating said pellet fermented biomass into a minimum solution (saline, phosphate buffer, H 2 O, etc.), preferably comprising a lactate salt, and allowing further fermentation at a temperature ranging from 4 to 40° C., for 12 to 36 hours, preferably for about 24 hours, to get a further fermented biomass; 
     d) separating said further fermented biomass from a second fermented product by centrifugation. 
     First and/or second fermented product obtainable from step b) or d) respectively are an object of the invention and collectively will be defined as “fermented product”. They may be used as active ingredients for the composition and the eye drop formulation, either individually or combined. 
     It is within the scope of the invention a method for treatment of eye inflammation syndromes, preferably of conjunctivitis, in particular of Vernal Keratoconjunctivitis (VKC), in human and veterinary medicine comprising the administration of the composition of the invention to a subject in the need thereof. 
    
    
     
       The invention will be illustrated by means of non-limiting examples with reference to following figures. 
         FIG. 1 : Mass spectrometry profile of fermented product of  Lactobacillus Paracasei  strain CNCM I-5220 obtained by SACI technique. 
         FIG. 2 : MoDCs were stimulated with LPS (100 ng/ml) and treated with or without fermented product of  Lactobacillus Paracasei  strain CNCM I-5220 for 24 h. Concentrations of IL-10 and IL-12p70 were determined by ELISA. Each symbol refers to individual donors. 
         FIG. 3 : MoDCs were stimulated with LPS (100 ng/ml) and treated with or without fermented product of  Lactobacillus Paracasei  strain CNCM I-5220 for 24 h. Concentrations of di IL-12p70, IL-10, IL-1 (3, TNF-α, IL-6 and MCP1 were determined by ELISA 
         FIG. 4 : MoDCs were stimulated with LPS (100 ng/ml) and treated with Flac or the control containing mannitol and sodium-lactate for 24 h. Concentrations of IL-10 and IL-12p70 as determined by ELISA. p**&gt;0.01 (two-ways ANOVA-Bonferroni) 
         FIG. 5 : MoDCs were infected with  Salmonella  SL1344 (MOI 1:1) and treated with Flac or the control containing mannitol and sodium-lactate for 1 hour. After that,  Salmonella  was inactivated with gentamicin (100 mg/ml) and, after 24 h of incubation, cytokine abundance (IL-10 and IL-12p70) was evaluated in culture medium. Concentrations of cytokines were determined by ELISA. 
         FIG. 6 : PBMCs were stimulated with LPS (100 ng/ml) and treated with fermented product of  Lactobacillus Paracasei  strain CNCM I-5220 for 24 h. Concentrations of IL-10, IL-12p40 and TNF-α were determined by ELISA. Panel A refers to the absolute concentration of cytokines, while panel B, shows percentage of cytokines referred to LPS-treated only cells. 
         FIG. 7 : PBMCs were stimulated with LPS (100 ng/ml) and treated with Flac or the control containing mannitol and sodium-lactate for 24 h. Concentrations of IL-10, IL-12p40 and TNF-α were determined by ELISA. p*&gt;0.05 (two-ways ANOVA-Bonferroni) 
         FIG. 8 : Mice were pre-treated with different doses of Flac (3.5 and 0.35 mg/ml) or its control, containing Mannitol-Sodium Lactate, during 4 days. After that, mice were injected intraperitoneally with 200 μg of LPS. After 5 h, the mice were sacrificed and levels of different cytokines (IFN-γ, IL-10, IL-12p40, IL-6, TNF-α and IL-12p70) were determined by CBA BD Array (BD bioscience). **p&lt;0.01. Mann-Whitney U Test. 
         FIG. 9 : Human primary corneal epithelial cells (HCEC, # C0185C Thermo Fisher Scientific) were stimulated for 24 hours with 100 ng/ml of LPS or  Staphylococcus aureus  Cowanin with or without fermented product of  Lactobacillus Paracasei  strain CNCM I-5220, Cytokine production (IL-1β, IL-8, TNF-α ed IL-6) was measured by ELISA in cell culture supernatant. 
         FIG. 10 : ZO-1 expression was evaluated by immunofluorescencence on Caco-2 cells. In the upper row images of cell treated with control; in the lower row cells treated with fermented product of  Lactobacillus Paracasei  strain CNCM I-5220. Each row shows triplicates of the same treatment. 
     
    
    
     MATERIAL AND METHODS 
     LC/MS Analysis 
     Mass spectrometry profile of fermented product of  Lactobacillus paracasei  strain CNCM I-5220 was obtained by Surface-activated chemical ionization (SACI) technique (J Mass Spectrom. 2005 December; 40(12):1550-7.). Fermented product from  Lactobacillus paracasei  strain CNCM I-5220 were treated as follow. Liophilized supernatant were diluted in PBS buffer and 5 μl were loaded on HPLC Ultimate 3000 (Dionex) equipped with Phenomenex Luna C18 (2.0×50 mm—particle size 3 μm) column coupled with HCT Ultra (Bruker) spectrophotometer. 
     Bacteria Culture 
       Lactobacillus paracasei  strain CNCM I-5220 was cultured in 3 mL of MRS medium anaerobically overnight at 37° C. The following day the culture was restarted (usually at a 1:10 dilution) and the bacteria were harvested and used for stimulation at the exponential growth phase, namely when OD was 0.6 as measured with an Eppendorf biophotometer.  Lactobacillus paracasei  strain CNCM I-5220 supernatants were obtained growing bacteria to OD600=0.6 in MRS and suspending biomass in saline solution supplemented or not with sodium lactate (Flac). The resulting medium was then filtered. Fermented product was maintained in liquid form or lyophilized by adding Mannitol. 
       Salmonella  serovar  typhimurium , strain FB62 was grown in 3 mL of Luria-Bertani broth and cultured aerobically (in agitation) and used for stimulation at the exponential growth phase, namely when OD was 0.6 as measured with an Eppendorf biophotometer 
     Monocyte-Derived Dendritic Cell (MoDC) Differentiation and Stimulation Conditions 
     DCs were derived from human peripheral blood monocytes selected with anti-CD14 antibodies coupled to magnetic beads (Miltenyi, Bologna, Italy). CD14+ cells were incubated for 6 days in complete medium containing granulocyte-macrophage colony stimulating factor (GM-CSF, 5 ng/mL; BD Biosciences) and interleukin-4 (2.5 ng/mL; BD Biosciences) in order to obtain immature MoDCs. MoDCs were incubated with Lipopolysaccharides (LPS) from  Escherichia coli O 111:134 (Sigma-Aldrich) or  Salmonella  FB62 (MOI 1:1 bacteria:DC) in the presence or absence of fermented product of  Lactobacillus paracasei  strain CNCM I-5220 for 24 h. Supernatants were tested for cytokine abundance by ELISA (R&amp;D systems) and by cytometric bead assay Flex sets (BD Biosciences). 
     Peripheral Blood Mononuclear Cells and Stimulation Conditions 
     Buffy coats were obtained from healthy donors having signed an informed consent for research use. Peripheral blood mononuclear cells (PBMC) were separated with Ficoll (GE Healthcare) gradient centrifugation and then resuspended and cultured in RPMI 1640 medium (Lonza) containing 10% fetal bovine serum (Gibco), 1% Glutamine 1% pyruvate, 1% non essential AA and 1% Penicillin-Streptomycin. PBMCs were incubated with Lipopolysaccharides (LPS) from  Escherichia coli O 111:64 (Sigma-Aldrich) in the presence or absence of fermented product of  Lactobacillus paracasei  strain CNCM I-5220 for 24 h. Supernatants were tested for cytokine abundance by ELISA (R&amp;D systems) and by cytometric bead assay Flex sets (BD Biosciences). 
     Human Primary Corneal Epithelial Cells and Stimulation Conditions 
     Human primary corneal epithelial cells (HCEC, # C0185C Thermo Fisher Scientific) were plated in 96 well plate at 10000 cells/well in the presence or absence of  Lactobacillus paracasei  strain CNCM I-5220 fermented product. After 24 hours cells were stimulated with 100 ng/ml of LPS from  Escherichia coli O 111:B4 (Sigma-Aldrich) or 1:1000 dilution of  Staphylococcus aureus  Cowan I for additional 24 hours. Cytokine production (IL-1β, IL-8, TNF-α ed IL-6) was measured by ELISA/CBA in cell culture supernatant. 
     Caco2 Cells Culture and Stimulation Conditions 
     Caco2 cells were cultured in DMEM supplemented with 10% FBS, 1% Glutamine, 1% nonessential aminoacids, 1% Penicillin-Streptomycin. Cells were seed in Permanox Plastic Nunc™ Lab-Tek™ Chamber Slide System (ThermoFisher) and stimulated with 100 ng/ml of LPS from  Escherichia coli O 111:64 (Sigma-Aldrich) in the presence or absence of fermented product of  Lactobacillus paracasei  strain CNCM I-5220. ZO-1 expression was evaluated by immunofluorescencence staining with the following monoclonal antibody: anti ZO-1 clone ZO1-1A12, Invitrogen, at a concentration of 5 μg/ml for 1 hour at room temperature. Slices were then incubated with the appropriate fluorophore-conjugated secondary antibody. 
     Before imaging, nuclei were counterstained with 4′,6-diamidin-2-fenilindolo (DAPI). 
     LPS-Induced Endotoxic Shock 
     C57/BL6 mice were purchased from Charles River laboratories. All mice were maintained in microisolator cages in a specific pathogen-free animal facility. All experiments were performed in accordance with the guidelines established in the Principles of Laboratory Animal Care (directive 86/609/EEC) and approved by the Italian Ministry of Health. 
     Mice were treated orally with Flac (fermented sodium lactate by  Lactobacillus paracasei  strain CNCM I-5220) at 96, 72, 24 and 2 hours, before LPS administration (n=5 per group). Control mice received Mannitol-sodium lactate. LPS from  Escherichia coli O 111:64 (Sigma-Aldrich) was injected intraperitoneally (i.p.) at 200 μg per mouse in 200 μl of injectable water. After 5 hours mice were euthanized by exsanguination under anesthesia and blood was collected. IFN-γ, IL-10, IL-12p40, IL-6, TNF-α and IL-12p70 levels were detected in the serum by CBA BD Array (BD bioscience), according to manufacturer&#39;s instructions. 
     Statistical Analysis 
     Student&#39;s paired t test (Mann-Whitney U Test) or ANOVA, was used to determine the statistical significance of the data. Significance was defined as *, P&lt;0.05; **, P&lt;0.01, ***, P&lt;0.001. Statistic calculations were performed with GraphPad Prism software. 
     Preparation of the  L. paracasei  821060 (CNCM I-1390, Redeposited as CNCM I-5220) Supernatant 
     An inoculum of  L. paracasei  B21060 is grown at a temperature of about 37° C. and is then gently stirred to avoid oxygenation of the culture medium, as MRS medium. The biomass is then allowed to grow for about 12 to 36 hours, preferably for about 24 hours, until the desired concentration of lactobacilli is reached (the preferred concentration corresponds to a microorganism growth equivalent to an absorbance of 0.6 at a wavelength of OD 600 ). Then, the culture is centrifuged to separate the bacteria from the culture first fermented product, the former being further processed as below for the preparation of the composition for eye drops of the invention. The first fermented product may be used to get the composition of the invention. 
     Preparation of Eye Drops Formulation A 
     Centrifuged bacteria are transferred to a minimum solution (saline, phosphate buffer, H 2 O, etc.) with or without sodium lactate (appr. 5 g/l/) and allowed to ferment for 12 to 36 hours, preferably for about 24 hours without agitation. Then bacteria are centrifuged to separate them from the, second fermented product and the latter is used in the preparation of the composition of the invention. For example the composition is used for eye drop formulation A, and consists of the second fermented product, diluted to 2-40% vol, preferably 10-25% vol, more preferably 25% vol, in a saline solution or other diluent suitable for the purpose, and properly filtered. The % dilution depends also from the bacteria concentrations obtained according to the above paragraph.  FIG. 1  shows a mass spectrometric profile obtained by surface-activated chemical ionization (SACI) technique. [Cristoni S, Rubini S, Bernardi L R. Mass Spectrom Rev. 2007 September-October; 26 (5): 645-56.] 
     Stimulation of Monocyte Derived Dendritic Cells in the Presence or Absence of  L. paracasei  821060 (CNCM I-5220) Fermented Product. 
     Dendritic cells (DCs) are professional antigen presenting cells involved in the induction of an immune response. According to the type of cytokines that they produce, DCs can skew the T cell response towards different polarizations, including interferon-(IFN)-γ producing T helper (Th)1 T cells, interleukin (IL)-4 producing Th2 T cells, IL-10 producing T regulatory cells, or IL-17 producing Th17 T cells. Each one of these cell types is responsible for distinct immune responses. In particular, Th2 T cells are involved in controlling the growth of parasites, Th1 in bacterial and viral infections, while T regulatory cells protect from inflammation and tissue damage. In humans, the most studied DCs are the ones that are generated from monocytes: monocyte derived (Mo)DCs. The activation of MoDCs with bacterial derived lipopolysaccharide drives DCs to produce both inflammatory (IL-12) and anti-inflammatory cytokines. Here it is shown that coincubation of MoDCs with a fermentation product of  L. paracasei  obtained under a non-canonical temperature amplifies the production of cytokines by MoDCs, including IL-12p70 and IL-10 ( FIG. 2 ). It also promotes the increase of IL-1β, IL-6 and TNF-α, but not MCP-1 ( FIG. 3 ). Similar results have been obtained also using as substrate sodium lactate (Fermeted Lactate, Flac) in response to LPS ( FIG. 4 ). When  Salmonella Thyphimurium  was used as stimulus, a slight increase in IL-12p70 was observed and no change in IL-10 production ( FIG. 5 ). These results indicate that the  L. paracasei  fermented product has a strong immune modulatory activity on MoDCs which however is not skewed to either inflammatory or anti-inflammatory response. 
     Stimulation of Peripheral Blood Mononuclear Cells in the Presence or Absence of  L. paracasei  821060 (CNCM I-5220) Fermented Product. 
     Peripheral blood mononuclear cells (PBMC) are a heterogenous cell population that includes myeloid as well as lymphoid immune cells. The amplification of the immune response observed on MoDCs suggests that  L. paracasei  fermented product may foster the activation of an immune response. In fact, when tested on PBMCs, the  L. paracasei  fermented product led to increase of IL12p40 cytokines without affecting the already high levels of IL-10 ( FIG. 6 ). Similar results have been obtained also using as substrate sodium lactate in response to LPS ( FIG. 7 ). Together, these data suggest that the fermented product may activate DCs on one side for a proper activation of an immune response, and maintaining elevated level of IL-10 which protects the host from immunopathology. 
     In Vivo Administration of  L. paracasei  821060 (CNCM I-5220) Fermented Product Modulates LPS Induced Cytokine Production. 
     LPS administration in vivo in mice induces what is called a cytokine storm that can lead to endotoxin shock. When mice were administered first with  L. paracasei  B21060 fermented product (Flac) and then with LPS we observed an increase in IL-12p40 and IL-10 and, as expected, no change in cytokine IL-6, TNF-α and IFN-γ ( FIG. 8 ). This suggests that  L. paracasei  fermented product does not influence the induction of protective Th1 responses and by increasing IL-10 production it does not induce overt inflammation. 
     Stimulation of Corneal Epithelial Cells in the Presence or Absence of  L. paracasei  821060 (CNCM I-5220) Fermented Product. 
     Corneal epithelial cells protect the inner chamber of the eye from the infection by microorganisms. These cells produce a series of inflammatory cytokines that can mediate the inflammation.  L. paracasei  B21060 fermented product can inhibit the inflammatory response in corneal epithelial cells in response to LPS. Epithelial cells were stimulated with LPS in the presence or absence of  L. paracasei  B21060 fermented product and cytokine production was tested. As shown in  FIG. 9 ,  L. paracasei  B21060 fermented product could drastically reduce the production of IL-8, IL-1β, TNF-α, IL-6. This indicates the  L. paracasei  B21060 fermented product interferes with the production of inflammatory cytokines and counteracts inflammation. 
     Analysis of Tight Junction Proteins after Stimulation of Epithelial Cells in the Presence or Absence of  L. paracasei  821060 (CNCM I-5220) Fermented Product. 
       FIG. 10  shows in the top line the epithelial cell images of three different experiments and treated only with a control solution, while the corresponding inferior line images show the same cells, this time treated with the supernatant of the invention. From the examination of these images we observe that tight junctions are modulated positively (upregulated) as a result of the supernatant of the invention, notably showing greater barrier properties. 
     Mucosal sites contain highly specialized epithelial cells, that are sealed by the presence of junctional complexes, including tight junction (TJ) and adherens junction (AJ). These form a tight physical barrier that maintains tissue homeostasis and protects from external insults. Alterations of junctional complexes are at the basis of several pathological processes.  L. paracasei  821060 fermented product favors TJ formation. Epithelial cells (Caco2) were grown to form TJ in the presence or absence of  L. paracasei  821060 fermented product and ZO-1 expression was analyzed. As shown in  FIG. 10   L. paracasei  821060 fermented product favors TJ formation by increasing ZO-1 expression. This suggests that  L. paracasei  821060 fermented product can potentiate the formation of epithelial barrier protecting the tissue from external insults. 
     Sequences 
     In the following are disclosed five gene sequences, representing specific core genes of  L. paracasei  and  L. casei  species. 
     
       
         
           
               
            
               
                 SEQ ID 1 
               
               
                 ATGAATCAAAAAGCTTTGAATCAATTTCCTGAACTTACCTACACAGAACA 
               
               
                   
               
               
                 AGTGTCGGTTGTTGGCGGCGATTTGTCAGTCGAAGTCATCATGAAAGGTA 
               
               
                   
               
               
                 TCTTCACCGGTATCTTTGATGCTGGGTACCAAGTGGGTCAGTCAATCGCA 
               
               
                   
               
               
                 AAATGGGTTAAGTAA 
               
               
                   
               
               
                 SEQ ID 2 
               
               
                 ATGAATCAAAAAGCTTTGAATCAATTTCCTGAACTTACCTACACAGAACA 
               
               
                   
               
               
                 AGTGTCGGTTGTTGGCGGCGATTTGTCAGTCGAAGTCATCATGAAAGGTA 
               
               
                   
               
               
                 TCTTCACCGGTATCTTTGATGCTGGGTACCAAGTGGGTCAGTCAATCGCA 
               
               
                   
               
               
                 AAATGGGTTAAGTAA 
               
               
                   
               
               
                 SEQ ID 3 
               
               
                 ATGCCCAAAAGGGTCGATCAACATATACGTTCACGCCTTAAAGGCTTTAC 
               
               
                   
               
               
                 TTTAATTGAAGTGGTGGTCAGCCTGATTTTACTTGCGGCGGTCATGCTGT 
               
               
                   
               
               
                 TATGGCGACCGGTTTTATTGCATGTCACGCGGTTCACGCTTCAAGACCAT 
               
               
                   
               
               
                 GTGCTAATCACGTCATTGCAAGCAGAGCATGACTTGCAAATGTTTGTACG 
               
               
                   
               
               
                 AGATAAAAAGTTGCGGTCTGTGGCCTTAATGTCGGTAAGGGTGAGAAGTC 
               
               
                   
               
               
                 CCGAGAAAGCTTACACGATCAATTTTTATCAGACCAAACATTTTCGCGGT 
               
               
                   
               
               
                 ATGGTTCGTGTGATGGGATCTGAAAATGGGCATATGCCATTATTTACGCA 
               
               
                   
               
               
                 TCTAACCGGTGTCAATTTTAGCAAGGTAGCTCAAGGCTTTCGCTATCGTC 
               
               
                   
               
               
                 TGTATTTGACGACTTCGCAGAAGATTGACGGTGGGGTGCAAATCGATGAA 
               
               
                   
               
               
                 GATACGCGGTAG 
               
               
                 SEQ ID 4 
               
               
                 ATGGCCGCTGATTTCACCCAATTACAACAAGCCATTCGCTTGCTCAATGC 
               
               
                   
               
               
                 CCATACTCGAGCTGCTGATGAGCAAGCGTGGCAAGTGCTTTTTGATCGTT 
               
               
                   
               
               
                 GGCTGGCAACTTTATCCTCTGAAACTCGCCGGCAAATGCAAACAGTTCGG 
               
               
                   
               
               
                 TTTAATCATGCCCAATTGACGTTACTCACAACGCTGGATCAAAGCAGTCG 
               
               
                   
               
               
                 CAAACAACTGCGCAATCAGGATTTAACCGCTGCTGTTCCGTTCTCACAAG 
               
               
                   
               
               
                 GCCTAGTCTCACGCTATGTTGCTCGCCTTGTTCAATTAAACTTGCTGACA 
               
               
                   
               
               
                 AAATTATCCTTGCCCGACAATCGCAAGGCCTACATTGTTGCACTAACTCC 
               
               
                   
               
               
                 GCTTGGTCAACAAGTCGCTGCCTTACATCAGCAAATGCATCATCACACAA 
               
               
                   
               
               
                 ATGCTCAACTCGCCTCTGTACTTCATACCCTTGATCCACAAGATGTTCAA 
               
               
                   
               
               
                 ACTACCATTCAGGTACTCACAAAACTGACGGCTCAGCCTTTACATCCCAA 
               
               
                   
               
               
                 GTCTTAG 
               
               
                   
               
               
                 SEQ ID 5 
               
               
                 ATGGGCGGTGTCATTTGTTACGCGGTGCCGGTCTTTTGGAAAAGAATACT 
               
               
                   
               
               
                 TCGCAGACACCTGATTCACGAGATTAAGACCCTGAATCAAGGATTGCAGT 
               
               
                   
               
               
                 TATCAAGCAAAGCCATGAGCCAATTAATTGATCCGGAAAATCCTTATATG 
               
               
                   
               
               
                 GTATTTGCTGATGAAAATGGTGAACTGGATTTTTCATTTTTGTGGCTAGG 
               
               
                   
               
               
                 CAACTTGCGTCAATTGAGGCGTGAACTGCGTCTAATTAAAGAACAGAAAG 
               
               
                   
               
               
                 CTAGGGTTTGA 
               
            
           
         
       
     
     In the following are disclosed unique sequences of  L. paracasei  B21060 with respect to the  L. paracasei  species publicly available in NCBI databases. SEQ ID 6 to 8 refers to gene sequences, whereas SEQ ID 9 to 18 refers to genome DNA sequences. 
     
       
         
           
               
               
            
               
                 SEQ ID 6: 
                   
               
               
                 ATGAGTAAATATAAAGTTATTATTTGGGGATTAGGAAACGTTGGTCGTTCCGCAGTGAGAATGAT 
               
               
                   
               
               
                 CGCGGAAAGACAAAATATTTTTGAATTGGTTGCAGCCGTTGACGTTGATCCAAAGAAGTTAGGTA 
               
               
                   
               
               
                 AGGATGCCGGAGAAGTCTTTGATTTTGACAAAGTCGGCGTCAAAGTTTCAGATGATATTGATGCA 
               
               
                   
               
               
                 GCCTTGAAACTTCCAGCTGACATTGTGCTCGACTTTTGCCCAACGGAAATGGACAAACAAGGAAC 
               
               
                   
               
               
                 ATTCATGCCTTCTGCTATTCGACTCGCCAAATCGCTCGATGCCGGTAAAAACGTTATTACCACGA 
               
               
                   
               
               
                 TTCCGGTATATCATGTTCAAGACAGTCAGCCAGAAGTATATGAATATCTAAATGAACATGCTAAAG 
               
               
                   
               
               
                 CACATAATGTTGCTTTTGTACCATTTGGACTTTTGCCAGGCGATTATGCCTCATATATCCCACTAG 
               
               
                   
               
               
                 TTTTGGCCGGGGCCATGGGCCACGTGGATAAAATTGTTGTTCAATCCGGTGAAGATGACTGGCA 
               
               
                   
               
               
                 CAACACATCAGGCTGGGTCGATGTCTTCTCATATGGCGGCGATATCAATAAATATCCAAAACCAG 
               
               
                   
               
               
                 ACTCAGACGAAGATCTCTTGGCTAAGTTCATTTATGCTTATTATTCATCCGGCGTATACGAGATGG 
               
               
                   
               
               
                 CCGATAGGATCGGTCTGAAATATGATACCTTCAAACCAGAGCATGAAGTCTTCACTGCACCCAAA 
               
               
                   
               
               
                 GATTTGGAAACGATCAAGGGTACAGTCAAAAAGGGCAGCATTTATGCCCACAGATTTACCATGGC 
               
               
                   
               
               
                 ACTTTACAACGGCAACGAACAAGTAGCCGCCTTAAGATATGTTCATAAAGTTGATAATAAAGAGA 
               
               
                   
               
               
                 CACCAGAATTACCGATCAATAATACGATTCATATTGAAGGCTTGCCGTCAGTCGATGCGCAGATC 
               
               
                   
               
               
                 GATGGATTGATCCCAGAAAGAGAAGGCTACGTTTCATCAGCCGCTCCAGCAGTCAACTTGATCC 
               
               
                   
               
               
                 CTAGCATTCTCGAGACCGACAAGACAGGTTATGTTGAAGTCTGCGACCTTCCAGTAGTGATTGCC 
               
               
                   
               
               
                 AGGCCATTGGATATTGGCGCAAAAAAATTAGTCTAG 
               
               
                   
               
               
                 SEQ ID 7: 
               
               
                 ATGGCAACCTATTCGCAGATAGAACTAGACATAATCAAATCATTTAAAGGGCTGATGAAAGACCA 
               
               
                   
               
               
                 TGAATTCACTGAGATCTCAATTAAAATGATCGCTGAAAAAGCCGATATCACTCGACGCGGCTTTTA 
               
               
                   
               
               
                 CAATCACTTCTTAGATAAATATGATCTTGTCAGTACCATCTTTGAGCATGATCTTTTTCCAACAGTC 
               
               
                   
               
               
                 ATCAGTTTGACGAATATCAATGACTGGGATCAAGGGTCGCTGTTTATCGTGAATTATCTCCAAGA 
               
               
                   
               
               
                 CAATCGCGACTACTATAAAAAATTGTTGTCGCTTGAAGGACAAAACTGTTTACAGACAGACTTTTA 
               
               
                   
               
               
                 TAAATTGACTGAGATGCAGATTGGGATCTTGATCCCAGAAATATTGGTCGGTAGGAAAATTTCTG 
               
               
                   
               
               
                 ACGAAGATCAGGCATTTTTAAGCGATTATTATTTTCACGCTTATATGGGACTGACTACCGAATGGG 
               
               
                   
               
               
                 TCAAAGGTAAATATGGTTTTTCAACTCAGGAGTTCGTTAAACGGTGGAAAGCCTTACTCAATAATT 
               
               
                   
               
               
                 CAATGCATAATTATCTGGACAACTACGCTCGATGA 
               
               
                   
               
               
                 SEQ ID 8: 
               
               
                 ATGAGTAAATATAAAGTTATTATTTGGGGATTAGGAAACGTTGGTCGTTCCGCAGTGAGAATGAT 
               
               
                   
               
               
                 CGCGGAAAGACAAAATATTTTTGAATTGGTTGCAGCCGTTGACGTTGATCCAAAGAAGTTAGGTA 
               
               
                   
               
               
                 AGGATGCCGGAGAAGTCTTTGATTTTGACAAAGTCGGCGTCAAAGTTTCAGATGATATTGATGCA 
               
               
                   
               
               
                 GCCTTGAAACTTCCAGCTGACATTGTGCTCGACTTTTGCCCAACGGAAATGGACAAACAAGGAAC 
               
               
                   
               
               
                 ATTCATGCCTTCTGCTATTCGACTCGCCAAATCGCTCGATGCCGGTAAAAACGTTATTACCACGA 
               
               
                   
               
               
                 TTCCGGTATATCATGTTCAAGACAGTCAGCCAGAAGTATATGAATATCTAAATGAACATGCTAAAG 
               
               
                   
               
               
                 CACATAATGTTGCTTTTGTACCATTTGGACTTTTGCCAGGCGATTATGCCTCATATATCCCACTAG 
               
               
                   
               
               
                 TTTTGGCCGGGGCCATGGGCCACGTGGATAAAATTGTTGTTCAATCCGGTGAAGATGACTGGCA 
               
               
                   
               
               
                 CAACACATCAGGCTGGGTCGATGTCTTCTCATATGGCGGCGATATCAATAAATATCCAAAACCAG 
               
               
                   
               
               
                 ACTCAGACGAAGATCTCTTGGCTAAGTTCATTTATGCTTATTATTCATCCGGCGTATACGAGATGG 
               
               
                   
               
               
                 CCGATAGGATCGGTCTGAAATATGATACCTTCAAACCAGAGCATGAAGTCTTCACTGCACCCAAA 
               
               
                   
               
               
                 GATTTGGAAACGATCAAGGGTACAGTCAAAAAGGGCAGCATTTATGCCCACAGATTTACCATGGC 
               
               
                   
               
               
                 ACTTTACAACGGCAACGAACAAGTAGCCGCCTTAAGATATGTTCATAAAGTTGATAATAAAGAGA 
               
               
                   
               
               
                 CACCAGAATTACCGATCAATAATACGATTCATATTGAAGGCTTGCCGTCAGTCGATGCGCAGATC 
               
               
                   
               
               
                 GATGGATTGATCCCAGAAAGAGAAGGCTACGTTTCATCAGCCGCTCCAGCAGTCAACTTGATCC 
               
               
                   
               
               
                 CTAGCATTCTCGAGACCGACAAGACAGGTTATGTTGAAGTCTGCGACCTTCCAGTAGTGATTGCC 
               
               
                   
               
               
                 AGGCCATTGGATATTGGCGCAAAAAAATTAGTCTAG 
               
               
                   
               
               
                 Position 102558..102986 
               
               
                 SEQ ID 9 
                   
               
               
                 AAAAACGGCTTAGAACGCTCATATTTGCGTTCTAAGCCGTTTTTATCAGCATAGGTTCTTGACACC 
                   
               
               
                   
               
               
                 AATAAACATCTTTAGTAATTGATCAAATTTAGGCAATGTGCTTTTGTCGGTGAATGGCGATAGCCC 
               
               
                   
               
               
                 TACCGAAGCTTCAGCTGAGGTTCTTCTGAGCCACGCAAGCGAAGCGCGCTAGGGCAAGCCAAC 
               
               
                   
               
               
                 GGCGCGCAGGCGAAGCCGGAGTTAAATGTGGCGCAGCCACACCTTTTTAGGGAGCAACGCGAC 
               
               
                   
               
               
                 CAGAATTTTGTATGGGGTTTGGGAAGAGGTTCTCCCCAAGGTCTTTTGTGGTTATTAACAAGCAA 
               
               
                   
               
               
                 AACACAAACACAAGCCTCGCGCGCGTTATATATACTTCTAAATACTTTTAAATACTTTAAGTACTTA 
               
               
                   
               
               
                 GGGAGACGAGAATGGCTCAACCACGCGTTTAAATCGACT 
               
               
                   
               
               
                 Position 103624..103864 
               
               
                 SEQ ID 10 
                   
               
               
                 ACGACCTCTCGACCACCCACTGCCTCACCAATCCCCAGGTGAACCGGGCCAAGGGCACTACCG 
                   
               
               
                   
               
               
                 AGCAACCCGACCCCTATATCCCGGTGGGCGTGGTGAAGCAGACCGATGGGGGCATCGTGGTGC 
               
               
                   
               
               
                 GGGGCGCGCGGATGCTCTCCACGCTGCCCACGGCGGATGAGCTTTTAGTCTTCCCCAGCACTT 
               
               
                   
               
               
                 TGCTCAAAGAAGGGCCGGGAGCCGACAAGTACGCCGTGGCCTTCGCCATCCC 
               
               
                   
               
               
                 Position 254291..261674 
               
               
                 SEQ ID 11 
                   
               
               
                 ATTGATCGCCTCCGGGTCACTTATATGTAACTAATAATACTCCCTTCTCTCTTTAGTTACAATAGG 
                   
               
               
                   
               
               
                 GTACAGCCTATCGAATCACTTACGCTTCCACTTTGAGATAACTTTTCGTTATTATTTATCAACGGC 
               
               
                   
               
               
                 ATTAACGATATCATTAACTGTTTGCAATGCATCGCTCAGTACACTAATTGGTGCTTGTTCAATATA 
               
               
                   
               
               
                 CTGCATGTGTCGTTGTACAAAATCAAAGGTGTGAAATTGTAACGGATTCACGTACCCTTCTATTTT 
               
               
                   
               
               
                 TTCAGTCTGAATCGGTACCATCAAGCCTGTTTCAGCTAAGCGATTATGTTTGGCATGCGTGATCG 
               
               
                   
               
               
                 GACAAACCAACGCTAATCCAGTCATTTTGGCATATTGTTGATTGCTAATAACGAGCGCTGGTCGT 
               
               
                   
               
               
                 CTTTTTTGAATTTCATGACCCCGACTTGGCATGAAATCAATACTCACAACATCACCTTTGCGTGGT 
               
               
                   
               
               
                 TGATAATGCCTAGTCCCACTCACTTGGTAATACCTCGTTTTCTAACGTAATATCTTGTTGGTGTAC 
               
               
                   
               
               
                 TTGTTGCTTGTACCAATCACCTTCAAATGGATTGCGGTGCTTCGGCAGATAAAGAATGCCACCAT 
               
               
                   
               
               
                 CATCACGTTGCTCAACTGTAAATTCAGTTCCATCGGCGATTTTAATACTCTTTGGAATGGTTAATG 
               
               
                   
               
               
                 TAATGGAATTGCCAACCCTTCTTGCTTTAACTGTCATTGAAATCATCCTTTCGTATACACCGAGTA 
               
               
                   
               
               
                 TACACCAGCGCGAATGAATCTGCAACTCTTGTGCCCTCTTGTGTACAAACACCACTGTCAATTTA 
               
               
                   
               
               
                 CTTTTGCCTATTGTGCTTTATCTCTTCTCGTTCTGTCATTAGTATGCCACCAACACGGCCGACTTC 
               
               
                   
               
               
                 ATCCGGCTCACCTTTGATGACGCCTTGAATACCATCGATTTGCTTCCAAGTCTTTACTTCCAAGTT 
               
               
                   
               
               
                 CTTCAAAGACTTTGATATCGTTTTTCGATGCCGGCAAACACTTCTTCATTCTGATGCCTTTCAAAG 
               
               
                   
               
               
                 AATTCCTCTAGATCATTCATCAGAGATTCTCCTCACTTAAACCTAGTTGGCGTCAAATTCCATCTC 
               
               
                   
               
               
                 AGCAATCGAATCTTCTAGGCTGTCCATTACTTCGTATGTTTCAATGAAGTTAACCCAGCTGTCATA 
               
               
                   
               
               
                 TGGATGTAGTTTGCTTTCTTTAATGCTAGTTCTAAGCTTTTCGTACACGTTGTCAATAAACTGCTCA 
               
               
                   
               
               
                 ACCATCCTATTAACCGCACTATTAATAACCGCTTCGTTCCACTGCTTAGATGCTGCACGCTTTCGA 
               
               
                   
               
               
                 TTTTGACTATGCTGATGGGACAGCGCCCGGCTTCTGAACAACGCTACTGCCCTGCTGTTAGCATT 
               
               
                   
               
               
                 CAGATAGGTTTCAAATTCTTCACGATCCATTACGTTTCCTCCTCAAAATAAGCCTCATTTCATAGC 
               
               
                   
               
               
                 ACAGCTTCAGCAAAAGGCATGTCATCCTACATGCCTTTTTTCTGTTGCTCTTCAATATCAGTATAA 
               
               
                   
               
               
                 AACGTCCTGCCGCTTTAGGCAAACGTATGTTCGCTATTAAGAACATACGTTTGTATAATAACTATA 
               
               
                   
               
               
                 AAAGATTTAAAGGAGGTCAATCGTATGGAAAACAATGTCCCGCGTGAAAAATGGCTTTACCCTGA 
               
               
                   
               
               
                 CCGCTGCATGAAGAAATGGCTGGGCTGGATTCTAAGCGACCATTCCGCCTATATGGAAGAAGCG 
               
               
                   
               
               
                 GCTATCTCAGAACAACCGGTGCTCCCAAAGCCTGAACAGACACAAGAAACCATTAATGGCGTACT 
               
               
                   
               
               
                 CGAAGATGCTTGGCAAAACTCAAAAATTGTCGCAGTTCAAATCGGTACGCCATACGATGATCTTC 
               
               
                   
               
               
                 TGTTACCGGATATTGAAGGCGCCGTGATTGGTCATTGGGACGCTCAGGTTTATCTACAGCTTAAA 
               
               
                   
               
               
                 ACTGGTGAGATGCAATCCATTAATGCAGCGGACATTCGCAATGTGCAACTGCTCAATCCAGATCG 
               
               
                   
               
               
                 GTGGTGGGCGTTAGTATGACGACACCATTAGATGATCCAACAAGGTTACCGGTACACGACATTAT 
               
               
                   
               
               
                 GTGCATTGACTGTAAGTCCTTTTACGCCTCAGTTGAAGCTATCAGACGCGGGATTCATCCGTTAG 
               
               
                   
               
               
                 CCGCCGACATTGCTGTTCTCAGCAAAGGTAATTCTCCTGGCGGTTTGGTGCTGGCTGCTAGTCC 
               
               
                   
               
               
                 CAACTGCAAAAAGCGTTACCACGTAGGACTGAGTACACGCCGTTTTCAGCTAAGGGACGATATG 
               
               
                   
               
               
                 TAGGTAGAACTTGCTGAACCGCGGATGGCTAATTACATTCGCAAGAATTACGGTATCAATCGTAT 
               
               
                   
               
               
                 TTACCGTCAGTTTACTGACGATGCTCACTGGTCTCCCTATTCCGTTGACGAGTCCTTTATTGACGT 
               
               
                   
               
               
                 TACCCACCCCCACAATCTCTTCGGTTCTAATGAAGAAATTGCTACCCAAATACAGAAGAAGGTGT 
               
               
                   
               
               
                 TTGATCAGTTTGGCATTGTCACAACAGTTGGCATTGGGCAAAATCCCCTATTGGCAAAATTAGCC 
               
               
                   
               
               
                 CTAGATAACGAGGCTAAGAAGTCAACGCCTTGGCAAGCCACTTGGACTTACGATCGTGTGCCAG 
               
               
                   
               
               
                 AAACAATATGGAAACTTGATGACTTGGTTGATTTTTGGTCGATTGGTAATCGAACTGCCAAGAAG 
               
               
                   
               
               
                 CTTAACGCGATTGGCCTTCATAATCTTTACGACTTGGCTCATGCAGACCGCGCCATTCTGCACCA 
               
               
                   
               
               
                 AAGATTCGGTGTTCTCGGTGATGCCATGTACTTTCACGCATGGGGTATTGATTACTCAGACTTAA 
               
               
                   
               
               
                 CCCGCCGCTACTTACCACGGGCCGAAAATAAAGGCTACGGCAATAGTCAGGTACTCATGCGTGA 
               
               
                   
               
               
                 TTACACTCAGGCAAGGGAGATTGAAGTCATGCTTAGCGAGATTGCTGATCAAGTGGCTGGCCGA 
               
               
                   
               
               
                 ATTCGCCATCACCAAGTCCAAGGTGAGGTCATTAGCGTTGGCATTGGTTATGCTGATGCAGAAGA 
               
               
                   
               
               
                 AGCTGGCACCTCCGGTTTCGGTGCGCAAATGAAGATTGATCCCACAAATCGCACAGACGATTTA 
               
               
                   
               
               
                 ATTCGCGCTACTCGATTTCTCTTCCATAGTAAGTGGAACGGACACGCTGTTAGAAATGTCTCAGT 
               
               
                   
               
               
                 TCGCGTTAATCGCATCAGCCAAGCAAGTACAATGCAACTTAGTCTATTTGAATCAGCAGAGAAGG 
               
               
                   
               
               
                 AGGAAGCAAACGCGGCTCCTATGCTGTAATTACGGATAAAAGAATCACCATCATTAGGTTTTTCG 
               
               
                   
               
               
                 TCTAACAATTTTAGGAAACTTCACTTTCTAGGTCGTAACTTTATTTTTGCAATCTAGGGTTTTTTAA 
               
               
                   
               
               
                 ATATATACATTTTAGCTCGTTTGTGTTTAATATTATAATCACAACTATACCAATGATAAATGTCTAAC 
               
               
                   
               
               
                 ATAAATATACAAACATGTTGACAGAAGCTCTTGAATACGTTTACAATTATTTCGTTCAGGCGAGCT 
               
               
                   
               
               
                 TTGTTTTTGAAAAAGTATTAATACAAGATAACTAGGTTAGTGGCTGTTGAATTAGGCCCCCGATTT 
               
               
                   
               
               
                 CGGGACCACGACAGTCACTTGATACTCGATTTTTATCGTTTGCTGGCTTGATCGTACATTGAACG 
               
               
                   
               
               
                 AAATTGGTACAGAAAAAAGAGCTAAGAGCCGCTCCAAATTAGCCAAAACGATTGCGGCGTCAATG 
               
               
                   
               
               
                 CTTACGGCGATCGTTTCTGCAGTTTTAGCTGTTACCAGATCAAGTCCTAGTTTCCCTTTGATGAAG 
               
               
                   
               
               
                 GCAAACTCACGCTCGATCTCACCTCGTCGATTTTCGGCTTGTCGGTCTGCCTTACGTTTGGCCG 
               
               
                   
               
               
                 GATCGACCTGCTTCGGCCGACGGCCCAATCTAGGACCGCTAAGTTTGATCCCAAGATCTGCGCA 
               
               
                   
               
               
                 CAGCCCGATATTCGCCCGAGTCCGATAAAGCGTATCAGCCAAGATCTCATCCGGGTATGTACCA 
               
               
                   
               
               
                 TACGTGTCAAAATAATGGTCGATCGTTGCTGGTAAGTCAGCACTTTCGTTAAACGCATTGAACGC 
               
               
                   
               
               
                 AAACCGTTCAACGGCCACGACGCCATGACTGATCGATACGTCGATCTTGGGCCCGAATTCGACC 
               
               
                   
               
               
                 GGATCCTTTGCTTTGCCGCGAATGATCGGTCGGATCGCTGGTTGATCAAGGCTTACGATCCGAT 
               
               
                   
               
               
                 CCGCGACTCGGTGAGTGTGCTGTCGATACATTTCAGTTTGTTGCTCATACAATTTTCGAATGATC 
               
               
                   
               
               
                 GTTAATCGTTGTGTCTGCCGTTGATTCAATTGCCCGCCTTGTGCTTGCAGTTCTTTGACGTAACG 
               
               
                   
               
               
                 CAAGTCACGTCGGATGTACTGTAATTGAGCCTTGATCTGCTTATGGGTCGTTTTCACCCAACGGC 
               
               
                   
               
               
                 GGGGTTTACGTGAAAAGGCGGTCCACGTTTGGTGGGCCTTGCGCTTATAGGTACGCGGCGGTTT 
               
               
                   
               
               
                 GACCGCTAATTGCTTGGCCATGGCTGCGATGAATCGCTCTAAATTGAGCCGCGCCTGATTGAGT 
               
               
                   
               
               
                 AGCTGCGTATCCTGCGGATACTTGATCTTTACTGGGACCGCAGTCGCATCAGTGATCAAGATCTT 
               
               
                   
               
               
                 CTGATGGCCAAGTTTAGCTTGGAGGCGATCGCGGACAAAATCGCTAATGATGTTCGTGATCAACT 
               
               
                   
               
               
                 CGGAAAGCGGCGCGATCCGGCGCCTGAAATAGGACAGCACCGAAAATGAAAACGGTGCTTGCG 
               
               
                   
               
               
                 GCTGATACTCTGGCAGGCCAATAAAATACTGATAAGCCGGTGTATCGCGGATCGCTGCGACTAA 
               
               
                   
               
               
                 CTCACGGTCCGATAGCTGAGTGCGCTGCTTGATCAGTTGGGCGCCATAAAGCAGCCGAAAGGG 
               
               
                   
               
               
                 TTTACCTGCCCATCCTAAGTTAGACGGGAAAGCCAATTGGTACGCCTCTTCTAGTTGCGGCCACG 
               
               
                   
               
               
                 GAACTTGGTCGGCCAGTTGGACCCACTCGTTATCTGGACTTAATGGGGTGCTTAAGCCGCTACC 
               
               
                   
               
               
                 AAACGATTTGATCGATAATTGAACGGCTTTTCGACGATAAACCATGATCCATGCCTCCGATAGGG 
               
               
                   
               
               
                 TCGTGTCAAATGCAAACGAAATGAGCACGATCCGTAAATTCATATGCATTCATTATACGACGATAA 
               
               
                   
               
               
                 CGGGTTCAACTCGCATCAAATGTGGTTATATCAAATTATTCAACAGCCACTAGGTTAAGATCTTCA 
               
               
                   
               
               
                 TTTAAGTGATATTCATTTGCAAGCAATTGAAAATTACTCATCACGAAGAGGATTTCATTGGCCATA 
               
               
                   
               
               
                 TTGGATAGCACGCAAATCACTTGCTTTAAGAAAATCAGTTCCTTTAATGAGTCTCTTAAAGGACGG 
               
               
                   
               
               
                 GGCTCTCACTTGTACTCACAATCAATGTTAACTGGAGATCAACAATATGGTCATAGATTCCCATAA 
               
               
                   
               
               
                 TAACATTGACTTGACTATCTAAAAGAGGCTTCTAACTTTGATATTGGTGGGGTTATTGGTTGCTTG 
               
               
                   
               
               
                 GCTGTAAGCAGATAATCTTAACTTGGGTTATTTTCATTGTGTTGTAAAGACATTTGTTATAAAGGC 
               
               
                   
               
               
                 CGAAGTTATCGCTTTGACTTGTAATAAATTATTTTTGATTGAGATATCAGAAAATAAACGGGGGAT 
               
               
                   
               
               
                 AATAATGAAAAAGATTATTAGGATTGTTCTTTGTGTTGTTAGTTGCGTTAGTATCATGGTCGGATC 
               
               
                   
               
               
                 GCTTGGGTTCTATTCAACTCCAAAGATCGTTAAAGCCGACAGTACATCTGTTACGGATGTCGACA 
               
               
                   
               
               
                 TTAATACCTATATTTCTAGCATGACACTTGATCAAAAAATTGGACAAATGTTTGTAGCACGAACCT 
               
               
                   
               
               
                 CACAAGATACTGATAAAGCTCGTGCTGATATAGCAAAATATAATCTTGGCGGGCTGATTGTTTATG 
               
               
                   
               
               
                 GTGTTGATTTCACTAGTGTTAAAGGGACAACAGCTACAGAAGCTCAGAATAACTTCAAGATGAAG 
               
               
                   
               
               
                 ATGCAAGGCTTTCAAAACTCGGCAAGTCTGCCACTATTGATTGGTGTTGATCAAGAAGGAGGGG 
               
               
                   
               
               
                 CAGTCTCACGCTTATCACAAAATCCTCTAATTGCCAACGGCAGAAGTTTTCCTTCACCACAAATG 
               
               
                   
               
               
                 GCTTATGCTAATGGTGGAATGACCAATGTAACAAAAGAAGCTAGTGAAGTCGGAACTATTCTAAA 
               
               
                   
               
               
                 AAATCTGGGCATTAACTGGAACTATGCACCAGTTGCCGACAGTACGCCTGACACCTCTAGTTTTA 
               
               
                   
               
               
                 TTTATGGTAGAACCTTTGGTCAAGATTACTTGGCTACTGCAAACTATATTACGAATGTGATCCCTG 
               
               
                   
               
               
                 CGTGGCAAAATGCTGGCATTGCCGCAACTCTCAAGCATTTCCCTGGTTATGGATCCGCGATTGAT 
               
               
                   
               
               
                 ACGCATACGGATTTTGCAGTCGTTACAAAGTCTAAGGAGGATTTTGAAAAAGAGGACTTGCTTCC 
               
               
                   
               
               
                 CTTTAAGTCCGGTATTACAGCAGGGGCAGATTCTGTAATGATTGCACATATAGTAATGCAAGCTG 
               
               
                   
               
               
                 TTGACCCAGTGTATCCAGCATCATTATCACGGAAGGTCGTTACCGATTTGTTGCGTAATGAACTT 
               
               
                   
               
               
                 GGGTATAATGGCTTAATAATTACCGATGCATTGGAAATGGGGGCCATCAAGCAATTTGCTCAAGA 
               
               
                   
               
               
                 ACATGATCAAGTTCCTGTTGATGTTCTTGCTGTTGAAGCAGGGAATGATTGCATCATGAATAACG 
               
               
                   
               
               
                 ATTATGAAACCGCTATTCCACAGATTCATGCAGCAGTAACTAATGGAACTATTAAGGAATCAGAAA 
               
               
                   
               
               
                 TCAATGAACACGTTTTCCGTATTCTTGATCTCAAACGCAAATTAGGGTTGTTAACTAAAGGACAAC 
               
               
                   
               
               
                 TTCAGCAAAAAAAAGTTCAGGTTGACAATGTTTCCTACAGCAGTGACAACAAAAAGGCAACTGTG 
               
               
                   
               
               
                 AGTGGAACAGTTGTTGATAGTGATTGGCAAGTTGGAGAACCATTATCGGTTAAAGACTCGACTGG 
               
               
                   
               
               
                 GAAGGTCATTATTACCGCAGACGTTGGTGCCGGTGGTAAGTTTACTTTCGATGTTCCTACTAAGT 
               
               
                   
               
               
                 CCCAAGAACAAGTATTAACTCTGACTACTAATTTACCCAACATCGCTGATTCTCAAATAACTATTAA 
               
               
                   
               
               
                 GGCTGTGAGTTCATCGAATACTAACAAAGCTTTGCTAGAAAACTTGATCAACGCTGCTGAACAGT 
               
               
                   
               
               
                 TGGATAGTAATCAATATACTGTCAAGTCGTGGGAAGAATTACAAACTAAACTAACTGAATCAAAAT 
               
               
                   
               
               
                 CGATTCTGAACAATGATAGTGCTACACAAGATCAAGTAGACGCTTCCGTTAATGCTCTACAAATTG 
               
               
                   
               
               
                 CCCTTAAGCAATTAGTTCCTGTATCAAATAGCGGAAATAATGGTCAAAGCTCTAATGATAGCAGTA 
               
               
                   
               
               
                 ACCAAAGTTCATCTAGCAGTAGTGGCAAAGAATCATCCAGCAATAGCAATGCCAATATTACTAGT 
               
               
                   
               
               
                 AAGGATCAGTCAGCTAAGGATTCAAATACGAGGCCTAAAGACCATAGTCTTTTGCCAAGTACAGG 
               
               
                   
               
               
                 TGAACGGGTGATGACGGGAATTTCTGTTCTAGGGGTAATTTTAATAGCTTGTGTGACTATATTATA 
               
               
                   
               
               
                 TATTCGGAAAAAAGGACGCAGCTTTTAATTAGTCTCTGCGTCAACTGGCGTTAAAAACTAGATTGA 
               
               
                   
               
               
                 AGTAATAAAGTTACCACCTGGAAAGAGGCATGCTCATTGCTTGCAAGGGTGTCGACGTGTAATAG 
               
               
                   
               
               
                 AAAAGTTGGGG 
               
               
                   
               
               
                 Position 325750..327159 
               
               
                 SEQ ID 12 
                   
               
               
                 TGGCGTGGGCAACGTGCACGTTTTCTAGTCGCTAAACTGTGAACAATGCTCGTGCTAAATGCAAA 
                   
               
               
                   
               
               
                 ACTGAGCAAGGAGATGAACTATAAGCGGGGGACCCTTTGCTATTGAGGAGGAAGGCGAAGTAGA 
               
               
                   
               
               
                 GAAAGAGCGGTGATTTGAACTCGAAACAGCGGCGCCGCAGGCTAGCAGCACTGTTAGATTAATC 
               
               
                   
               
               
                 GCCAGCAGCAGATACTAGACAGCTTCTTAAAGGCTTGATAATAGCGTTGCGCCATTTCAATGGAA 
               
               
                   
               
               
                 CTAGTGGTCAAAATCGCATTGTAGTTGCCATGACCCAAACTCGTTTTACGCGGGCCTTTTTGTAA 
               
               
                   
               
               
                 AATATATTGAACAACTTGGTTAATATGTTCATCGGTCTCAAAGTCAGCCGGAGTTAAATACGTTTC 
               
               
                   
               
               
                 TTCCAAGTCCTTCACTGACATCGCTTGAATCTTGGCTTGAATTTTCGCTTCATCAGCCGTACTCAG 
               
               
                   
               
               
                 CAGGCGGCCTTGCTTATCACGACGAGCTTTAACGCGCTGAGTTTCTTTTTCAAGGGCCCGGGTT 
               
               
                   
               
               
                 ATTAAAGCGTCTTTACCAATCGTTGTCACGTGTTCCACATTAAATGGTAACACTGCTTGGTCCTCT 
               
               
                   
               
               
                 AAGGCGTCTCGCAAGTTATAAACATGACAGACTTTACCAAATAGCTCCTCCGTCGTAACTGCTAG 
               
               
                   
               
               
                 ATCACCTTTGAGCTGTTTCTTATTTTCATTAAAAATGGGGGTGCCAGTGTAACCATACCAGTTACT 
               
               
                   
               
               
                 ATTGATAAACGCTGCTCGAATTTCCTTTTGCATCTTACCAAACTGCGACCGGTGGACTTCTTCAAC 
               
               
                   
               
               
                 AAAGAAGATCACCCGTTGCTTTAAAGTCTTACTAAAGCGGGATTGCTTACCGGTTGCCAGCTGGA 
               
               
                   
               
               
                 CTTGCGTTTTTTTGACCGCCCGATGGAGCTTTTGAATCGAGGTGACCAAGACCTTACCGTCATTT 
               
               
                   
               
               
                 TGTTGCAATTTACGCATTAAATCACCGGTGTTTTGGGCTTCGTTAATGGCAATATCATCATTGGCA 
               
               
                   
               
               
                 GCATAGGCACTAAAGTTGCTGGTTGTCTGTTCGTCTAAATCCCGCCGGTCAACTAAGAAGATGAC 
               
               
                   
               
               
                 CTTATCGACACCAGGATCTTGCGCAGCTAATTTAGCGGTTTTATATGAGGTGAGTGTTTTACCAG 
               
               
                   
               
               
                 AACCCGTGGTATGCCAAACGAAACCATCCTGATGGTCATGAATCCGGTGCATCACGGCTTCAAT 
               
               
                   
               
               
                 CGCATAAATCTGGTAAGGCCGTAAGAGAATTAAGCTTTGCCGCTCTTGGTCGATGACTGTATATT 
               
               
                   
               
               
                 CACTGACCATTTTGTGGGCCATGGGAATATTAAGGACTTGGCGCGTGAACGCTAACCCGTTTTCC 
               
               
                   
               
               
                 ACGGGGTGATTATCCCGCGTCCGCCAATTGAACAAAAAGGCTTTATTGAAATGATCCGGTTCGG 
               
               
                   
               
               
                 CATTCGCAAAATACGCCGTACTATCCGGCGTCATAATCACAAAC 
               
               
                   
               
               
                 Position 328723..329314 
               
               
                 SEQ ID 13 
                   
               
               
                 CGATCTAAAAGCTAAGTTATTTTCCAAGATATCAAACAACTTCTTAACCCAAGAATCTTCCACACAT 
                   
               
               
                   
               
               
                 AGGACAATAATGAATCCAAATAGATTCAGCTTTTTCCTGCAAACCGGGATCAGTATAAACGTCCA 
               
               
                   
               
               
                 GTACCGGATAATCACGCATTAAGTTCAGCTGCCAATGGGTATCATCTAAATTAAAAAGATCCGATT 
               
               
                   
               
               
                 TAGTGTCTCCCCTTACTACATTATGGCAATACACACAACTGTTGTTATACATGCTTCCTTGCTTTTT 
               
               
                   
               
               
                 GATTTTAAACTCCTCCATTTTGCATATTATAAGAAGATTACTTCTACTTGATATATAGATGCTTTCC 
               
               
                   
               
               
                 TTGCGAGGGTAAGTCAGACAAGGAAGCATTTCTAACTTGAGATACTTAAGCTTGTCTCAATAGAT 
               
               
                   
               
               
                 GTAGATAGCGGCTCCCCAATCGGATATTAACAGCTCAACTAGTCAAACCAGATATATAAATGTGA 
               
               
                   
               
               
                 CACAAGCTGGAATATATATCATTATCTAGATAATTCAAATTGAGCTAATAAAATCAATAAAGAAAAT 
               
               
                   
               
               
                 TTTAAATAACATTATTTTATAAACCCCTTTAGGATTTTCCCGATTTGATATTCTACGTATGTT 
               
               
                   
               
               
                 Position 2002858..2005090 
               
               
                 SEQ ID 14 
                   
               
               
                 GAGTATCCAAAAATACGACGGGTATTTGAATAGGATACTTATTAAGCGAGAATGGTATTGGAAAT 
                   
               
               
                   
               
               
                 CTGTGGCAGCCACTCAGCGGAACCATACCTTTATCCCAACCCCACGCAAAAAAAACATCAAGTAA 
               
               
                   
               
               
                 TCCGTCAGATATGATGACTTAATTGTGGGACAGTTCTAATATGAAGAAAACAGGTTAGATAATTGG 
               
               
                   
               
               
                 GGTGAAAAGATGGCAACCTATTCGCAGATAGAACTAGACATAATCAAATCATTTAAAGGGCTGAT 
               
               
                   
               
               
                 GAAAGACCATGAATTCACTGAGATCTCAATTAAAATGATCGCTGAAAAAGCCGATATCACTCGAC 
               
               
                   
               
               
                 GCGGCTTTTACAATCACTTCTTAGATAAATATGATCTTGTCAGTACCATCTTTGAGCATGATCTTTT 
               
               
                   
               
               
                 TCCAACAGTCATCAGTTTGACGAATATCAATGACTGGGATCAAGGGTCGCTGTTTATCGTGAATT 
               
               
                   
               
               
                 ATCTCCAAGACAATCGCGACTACTATAAAAAATTGTTGTCGCTTGAAGGACAAAACTGTTTACAGA 
               
               
                   
               
               
                 CAGACTTTTATAAATTGACTGAGATGCAGATTGGGATCTTGATCCCAGAAATATTGGTCGGTAGG 
               
               
                   
               
               
                 AAAATTTCTGACGAAGATCAGGCATTTTTAAGCGATTATTATTTTCACGCTTATATGGGACTGACT 
               
               
                   
               
               
                 ACCGAATGGGTCAAAGGTAAATATGGTTTTTCAACTCAGGAGTTCGTTAAACGGTGGAAAGCCTT 
               
               
                   
               
               
                 ACTCAATAATTCAATGCATAATTATCTGGACAACTACGCTCGATGAATTACACAGATTGGATTAAA 
               
               
                   
               
               
                 TGAGAAAGATGTTACATTTGTGCCAATATGTGAATTGATAAATATTTCACAAGGAACTATTCTTTCC 
               
               
                   
               
               
                 CTGTAAACGAAAGTTGACTTGAAAGGAGTTAGTTCTGATGAGTAAATATAAAGTTATTATTTGGGG 
               
               
                   
               
               
                 ATTAGGAAACGTTGGTCGTTCCGCAGTGAGAATGATCGCGGAAAGACAAAATATTTTTGAATTGG 
               
               
                   
               
               
                 TTGCAGCCGTTGACGTTGATCCAAAGAAGTTAGGTAAGGATGCCGGAGAAGTCTTTGATTTTGAC 
               
               
                   
               
               
                 AAAGTCGGCGTCAAAGTTTCAGATGATATTGATGCAGCCTTGAAACTTCCAGCTGACATTGTGCT 
               
               
                   
               
               
                 CGACTTTTGCCCAACGGAAATGGACAAACAAGGAACATTCATGCCTTCTGCTATTCGACTCGCCA 
               
               
                   
               
               
                 AATCGCTCGATGCCGGTAAAAACGTTATTACCACGATTCCGGTATATCATGTTCAAGACAGTCAG 
               
               
                   
               
               
                 CCAGAAGTATATGAATATCTAAATGAACATGCTAAAGCACATAATGTTGCTTTTGTACCATTTGGA 
               
               
                   
               
               
                 CTTTTGCCAGGCGATTATGCCTCATATATCCCACTAGTTTTGGCCGGGGCCATGGGCCACGTGG 
               
               
                   
               
               
                 ATAAAATTGTTGTTCAATCCGGTGAAGATGACTGGCACAACACATCAGGCTGGGTCGATGTCTTC 
               
               
                   
               
               
                 TCATATGGCGGCGATATCAATAAATATCCAAAACCAGACTCAGACGAAGATCTCTTGGCTAAGTT 
               
               
                   
               
               
                 CATTTATGCTTATTATTCATCCGGCGTATACGAGATGGCCGATAGGATCGGTCTGAAATATGATA 
               
               
                   
               
               
                 CCTTCAAACCAGAGCATGAAGTCTTCACTGCACCCAAAGATTTGGAAACGATCAAGGGTACAGTC 
               
               
                   
               
               
                 AAAAAGGGCAGCATTTATGCCCACAGATTTACCATGGCACTTTACAACGGCAACGAACAAGTAGC 
               
               
                   
               
               
                 CGCCTTAAGATATGTTCATAAAGTTGATAATAAAGAGACACCAGAATTACCGATCAATAATACGAT 
               
               
                   
               
               
                 TCATATTGAAGGCTTGCCGTCAGTCGATGCGCAGATCGATGGATTGATCCCAGAAAGAGAAGGC 
               
               
                   
               
               
                 TACGTTTCATCAGCCGCTCCAGCAGTCAACTTGATCCCTAGCATTCTCGAGACCGACAAGACAG 
               
               
                   
               
               
                 GTTATGTTGAAGTCTGCGACCTTCCAGTAGTGATTGCCAGGCCATTGGATATTGGCGCAAAAAAA 
               
               
                   
               
               
                 TTAGTCTAGACTAGGCTTTCGAAGCTGCTTTGACCATTAAGGTTGGAGTAGCTTTTTCATTTGCAA 
               
               
                   
               
               
                 GTAAATCATTACGGCTTGTGTATACGGTATACAAAATGGAGAAAACGCTGACTAGTTTATAAATCA 
               
               
                   
               
               
                 TTGAGACTTAACGGCCGGATAAATGCTGATCTGATTATAGAAATAACAACAAAAAGGCCACGCTA 
               
               
                   
               
               
                 AAAATCATATTAATTATAATCGGGAAATTTATTAATAATATTCAAGAAAAATAAAAACCGTGGGTAC 
               
               
                   
               
               
                 ATTATTTAAAA 
               
               
                   
               
               
                 Position 2262750..2268615 
               
               
                 SEQ ID 15 
                   
               
               
                 TTTGAAACTAAGACGAAAGCTGCCATGTCAAACAAAGCCGCCATAAATGCCACTGTCACA 
                   
               
               
                   
               
               
                 GATCCATCAGCCGCAATGCCAGCATCTTGCTGAAGTTCTTTAACAGCATTAAGGGTGTTA 
               
               
                   
               
               
                 TTCGTGAACTCATTATTAAAGTCTACTGGACTAATCCCTTTGCACCAGAAAGCCCCTTGA 
               
               
                   
               
               
                 ATGAGTTGAGCAATGTTCCCCTTATATCCTGGCTTCAGACTACCTACAACAGGTGCTAAG 
               
               
                   
               
               
                 GCGTTTTTGGTCGTCTCGCCAAAGCCTTCACCAATAGCACTAATACCGATTTCGTGCTGT 
               
               
                   
               
               
                 AATCCCATTCTTAGGCTATAAATTGTTGGCCATCCCGTTTGCCCGTTTTCTGGAGCTGCG 
               
               
                   
               
               
                 ACAAAGCCAGGAACGCTACCATACGTTTTGTTGAGCCATTTTTGAACGGCTCGTACTGCT 
               
               
                   
               
               
                 TCATCTGCCATTTTAAAGTCTCCTTTTTTGTTTTAGACAGCACGTCTGCCGTCACAAAAA 
               
               
                   
               
               
                 GCAAACATATGTTCGGATTCATTTCATCTCTTCAAAGCTTCGAAAGGCAACCCTGATCCA 
               
               
                   
               
               
                 CAAATAATCCTTTTATTTTGAACTTAGCAAAAAAATGAGGCCCTCACATAGTGTTGAAGT 
               
               
                   
               
               
                 TGCCTCATTCTTAATGTCTATATTTAAAGTATTGCCACAACGATGGATCATCGAACGCTC 
               
               
                   
               
               
                 ATGGACTTGGTTAGACATGTATCGACGACTATGAAAATGTGGGCGCAAGCTCAATTTCAC 
               
               
                   
               
               
                 CTTCCAAATGTTTGTGCTATCTCATTTAGCGCTGGTTTTTTTAGGATAGACTAGACAAGG 
               
               
                   
               
               
                 ACTAATAATTTCTCAAGAATCCCGCAACTCCACTATTCATTCGTCGAAATCCCCACTGAT 
               
               
                   
               
               
                 ACTCTTGTCCTTGCACGTTCGACCAAGCAAGAATGTTTATTCCGATAACCGAATTGTTGC 
               
               
                   
               
               
                 CATCAAGTAATGGACCTCCCGACATGCCATGATACGAATTAATTTGTTGTGAAATATATA 
               
               
                   
               
               
                 TTCCTAGTGGGTCCTCTGAAAAGGGTGTGACAGTCCCACTTGATTGAACCATGACTCCTT 
               
               
                   
               
               
                 GAAGTTCGTACCCTGATTGCGGATCGCCAGGGAATCCAATGGATCTTGCTGCCATCGTAT 
               
               
                   
               
               
                 CAGCAGGGTTCGTATTTAAATTAAGACCCGCAGGCATACTACCAGACTTCATAGAGACAA 
               
               
                   
               
               
                 TTGCAGCCCCGTAATCATTCGAAGTAGCTGTTGAATTATTAATCCATGCCTGTGGCACTA 
               
               
                   
               
               
                 TCAATCTATTCAATACTCCGTAACCGACCCCTTGATGATTTGCTTGACTATCACCAAAGT 
               
               
                   
               
               
                 TAATAATTCCTCCAGAAATATAATGACCATCATATAACATGTGTGCTGCTGTCCCTATAC 
               
               
                   
               
               
                 GGTCTACTCCAATGCTAAATCCAGTACCGCCAGAAGTTCCACTGCTCAGCTCTGTGCCAT 
               
               
                   
               
               
                 TTGAGTTAGAGATGATTTTTTTATACGAACTGTCAAGGTATGGTGAGTTAATGACCATGA 
               
               
                   
               
               
                 CACCATTTGCCATCGAAAACCACGTGCTCAAAACCCCAACGGAACTGTACGGCGCCGAAT 
               
               
                   
               
               
                 TGGGGTTTGACACAGGTGATACCGTCCTCACAGATAGATGATTAGACGATTTATTCAGTT 
               
               
                   
               
               
                 TCGCAAGATATTCGGACGTAATTCCTTGAACTTTCTTTCCTTCTTTTAAATCCTGATATT 
               
               
                   
               
               
                 GATCAGGTGTATAAGCTTTGACACTCCCTTTAAAATCGGGATAAGAATACTGATATTGTC 
               
               
                   
               
               
                 GAATGATTTCATTCAAAAACTGTTGTGTTGTCGTCTGGTTAGTCAAAACAATATCATTCT 
               
               
                   
               
               
                 TTGGTAAAACATGGCTATTCGCTGCCAAAGGATTTGCCATACTATCAGCACTTACACTTA 
               
               
                   
               
               
                 CCGTTTGAACTTGAATTATCGCTAAGGCTGCAGCTATCATAGTGATATATGCCCATACTT 
               
               
                   
               
               
                 TTCGCAATTTAATTCCCCCTTTTTCTTAAAATGAAACCGCATTCACGGAGGCTTGTCAAT 
               
               
                   
               
               
                 GCTTTTAAAAAACAAACGTTACTTTTGGCTCATCTTGGCTGTCAGCATAATTGGAGTAAT 
               
               
                   
               
               
                 TGTTCTTGCGGTGTTATGGCGCATGAACCCTGAAGGAACGGCCTCAAATAAGTTTGAACG 
               
               
                   
               
               
                 TCCCACCATTACTATTAAAAAAGTCAAACTTATTAAGCACAGTAACAGTATTGCTGTCAC 
               
               
                   
               
               
                 ATTTGCTACCTCTCCAAAAAGCAAATATACGATAAGTGATCTTAAAGAGAATCAACTTTC 
               
               
                   
               
               
                 TTCTGGCATTTCGAATAAAAGAGAAAATACCGTTTCGGAATTAAAGCCCTCCTCCTCTAA 
               
               
                   
               
               
                 GCTTGCAATACGGGTTAAGCATAACAATAATATACAAACCAAAGTGGTTTCTGTTCCCAT 
               
               
                   
               
               
                 TGGTTATCATATTATGAAAAGTGCCATTTCAAGAAAGCCAATTCCTATGGGAGAAGAGTT 
               
               
                   
               
               
                 TAAGTACAATGGAAAGTCGCATGTTTTATTTAGCATGACCATTACCCCTAAAAAACAAAA 
               
               
                   
               
               
                 CAAGAACAGTATAAAAAACACCACTGCTTTTAACATAACGGTTAAAAATGATCACTACCT 
               
               
                   
               
               
                 TGTCCCTGTCGTATTAGATACCAAATACCTTACTGTTTCTGATTCAGAAGGTAACTCATT 
               
               
                   
               
               
                 AAAAGTAAAGCCATTCTCAAAAATTTCTATTCCAGCAAAAAAGAAAAAGACCATTGCAAT 
               
               
                   
               
               
                 AACTATTGAGGGCGTTCCCGCAAGCTCTGCCAATGGTCTAGTTATAACGTATAATACTGT 
               
               
                   
               
               
                 CGATTTAGACTTACCAATCTCCTTTATAAATTCCTGAAATTACACTAACTGTCCCCCACC 
               
               
                   
               
               
                 TTGACAGTCAGTACACTCAAACTGTCTCTTATGCTTACAAACACGTAATTTAGGCGGTTT 
               
               
                   
               
               
                 TTAAGCAAAAGTCGTTAGTTTTCATAAATGTTATCTTATACTCTAATGAGATCTAGCTTG 
               
               
                   
               
               
                 TGATAATAAGGCTGTTTTTCTTTGACAGCCTTATTAAGCACACTAATCAATGTCAATTCG 
               
               
                   
               
               
                 AAGTTTTTGGTTTCCTACTTGGCCAACTTTGTTATCAGAAATTCCAAAACTCATTGCCTC 
               
               
                   
               
               
                 CCGCCACCATATATTTATCGAGCCATTTTGAAAATGAAAAATCGAAATATCGGTCTGCTT 
               
               
                   
               
               
                 CTATTCCGGGATGAGTTAGATATGATTTTCCTAACCGATACTTCTCTATATCAATATACA 
               
               
                   
               
               
                 TATCTCCGACATCCCTTATATGGAGAATGGGTACTTTATTTACAAAACTTTTAGGCAGTG 
               
               
                   
               
               
                 CCTCTTTTTCTTTAATCATTTTTCTAATTGAATAGACTTCACACGTATATCCCATAGGAA 
               
               
                   
               
               
                 TCCCTTCGATTGTTGTGTCAAATAAAAATAGTCCATTAGTAATCGAGAGAAACTCAATGT 
               
               
                   
               
               
                 AATCCTGTGGAAGGTTCCACCTTTTTATTTTTTCTATATCATCAGCGTGTGCAGGAGGTT 
               
               
                   
               
               
                 CTATCTTAAAAGAAACATTTTGCACATCTCCATCTAATTGGAATGTTGAGAGCGCTTTTT 
               
               
                   
               
               
                 CCCCATTTTTCGTCACCTTTATTAAAGAATTAATTCTTCGCCGAATTAGAGATTCCAAAT 
               
               
                   
               
               
                 GAGTTCCTCCTCAATAGTTGTTAAACCACGCGGTGATCAACCGATGATTTGGTGTTAACA 
               
               
                   
               
               
                 CCGGCATCAAATTATTAAAGTCATTTGTTCCGCCATAAACTCTCGGGCGAATATGATGCA 
               
               
                   
               
               
                 CTTCTCGAGAACTCCAAAAATCTGCAGATTGATTGCCATATGTTTCACTGAACGTTTTAA 
               
               
                   
               
               
                 TATAAATATATCTATCTTTTGATGACCAACTAGGAGATTTTGATAACTTAGTCCAGGTAG 
               
               
                   
               
               
                 TATTAATAGGTGTTTCTGCATCTTTTTTAGACACGGGATCAACATATTCAGGGAAATTCT 
               
               
                   
               
               
                 GTCCTATTTTATTTTGTAAATAGATGGCCGTTGGTGGGATTGGTTTTACATTAGCCGCTC 
               
               
                   
               
               
                 CATTAACTCCTATAAATCCAACAGCGCCAGCAACGTTAAAAAATGTGGTTTTGGCTGGCA 
               
               
                   
               
               
                 ATTCTGTAAAACCAAGTAATCCTGTTTGCAAACCGCCTATTTTGCTAATGGGTGCCAGCG 
               
               
                   
               
               
                 TATTGGCATTCACCGGACCTGCAAGGGTAGGCTCAGTATTAAATTCAATTTGCACATCAA 
               
               
                   
               
               
                 CTGCGGCTGGCGGGACACCCTCAATAGAATCAATCCAGAAATTGACTCTGAATTTTCCGG 
               
               
                   
               
               
                 ATATGTATTCTTCCGATAAGTGCCAGGTAATATTTGTAACAGGAACTTCTGCACGAGAAC 
               
               
                   
               
               
                 TTATGCCATTGCCATGACTATTATTCAGTACCACTTGTTTTCCAGAAGCGATAATTGGTT 
               
               
                   
               
               
                 GTCCATTTTCTGGATTACTTCTTGATAACTTGTCAGCATTGGTCAGTTGAGTATTGTTAT 
               
               
                   
               
               
                 CGCTAATACGGCTTTCAGTTGAAACAATTTGATTTAAAGATTGTGTTGTGTCTGCGGATA 
               
               
                   
               
               
                 CAATTGTTGAATACCCAAGCAAATTGACTAGAAAGAGCCCGAATATTAGCCCAATAACTT 
               
               
                   
               
               
                 TCCACTTTTTCACGCCTATTATCTTCTTTCCAAAGTTCTTCAGTGCCTGGCAATAACTGT 
               
               
                   
               
               
                 ATACATTGAGCAGTATAGTCGCTATTTTATAGCTGAACAACTCATAAAGCTCAATTATTA 
               
               
                   
               
               
                 TTAGCCTATAAAACCACTGCCTAAGTGAATTGATCTAGAACGAAGCACGCCGAAGAAGTC 
               
               
                   
               
               
                 GCTAAATGTGCTAAGAAAAATGTGCTTGAATAGCTCAAAAGTAATTAGCGTCTCCATTGA 
               
               
                   
               
               
                 AAATCCGTTATTTTTAAGTGATCTAGTGTTAACTATGAATCCCAAATAAAAAGCAAAATC 
               
               
                   
               
               
                 CGTAAATGCCAAATTTTCCTTTTTGACGTTTTTCTACTGTCGCGAGATTTGCAAGTGTAC 
               
               
                   
               
               
                 GTACACTTACGATGAATTGACAGAATCTCAGCTGCGCTGATCGTCAATTTTGTTTGGGGG 
               
               
                   
               
               
                 CACGCCCCCAATCCCCCTGTTATTTTGAAGGGAGGTGAGTCCCCCTTCAAAATCAAAATT 
               
               
                   
               
               
                 TAAACAGCATCTGCCGCCATCTTTTCGCTGACCTTCTCACGATGTTACACGTGGTGTTGA 
               
               
                   
               
               
                 CACCCACTTGCATTTAGAGTTTCATTCAAGTTGAACATTGTGTAATATATGAGTTGCATT 
               
               
                   
               
               
                 TGATAAACATATCAGTTGCTATTTGTGCAACTTTAAAGCTTCGGCTAATTCAACGTTCTG 
               
               
                   
               
               
                 TTAATTTACAAGCATCTCGACAGTTTCTGTTAAAGCAACATCTACGCTTCAATTCGAGCA 
               
               
                   
               
               
                 ACTCACTATACGTATGCCGAGTTGCAGACAAGCTACTATATAGCTGTACGCGCTGAAACA 
               
               
                   
               
               
                 CCAAAAATCGTTCGTTTATGCCCAATAAGCGAATAATCTTGCTCAGGTGTAGTAAAAAAC 
               
               
                   
               
               
                 TGTTTACGTGTAGTGAATGGCGCTAGCCCTTGTCGTAACTGGCATCATCCACGTGTAGTA 
               
               
                   
               
               
                 AAACGCGTTTTACTACACGTTCGTAATTTTTTCACGTGGAGTAAATGGCGTTTTACTACA 
               
               
                   
               
               
                 CCTTTTGACCCCAACGTGCTATCACGACAAACCAAACCGCACTGCGGTTTACCCCAATTT 
               
               
                   
               
               
                 TGGGGTCAGTTTTGCCTTATGCTCTTTCATGATTTTAGGCGCGTTCCAAGCAGTCTCAAA 
               
               
                   
               
               
                 AAGTGGTCGATCCAGGCGAGCCGATTTTTGAGAAGGATTGGATAGCAACTCAATTTATTT 
               
               
                   
               
               
                 TGATCTTTTGCTTGGAGAAAAACGTTCACGTTTTGACCAGGGCCGTCGCAACTGTTGACC 
               
               
                   
               
               
                 AAAACTCGTCCGGTAACGTGACGCTATTTAAACGCCGCGTTGGTTTGCTAGACGACCATT 
               
               
                   
               
               
                 CATCATCACCATTCAGGAGGTTTTTGAAATGACAAAGCAAGACGAAACACACCGGGTCAT 
               
               
                   
               
               
                 GTTCACTTTGACCGATCAGGCGATTGCAAAATTGAATCAGCTGGTCGCAAAAAAGCAACA 
               
               
                   
               
               
                 GGAAGTGAATCAAAATCCGGAACTGGCTAAGTACCATGTCAGCGTGACCAAATCAAATAT 
               
               
                   
               
               
                 CATTGAGGACTGGTTATCAAAGCAGTGAGTTTAAAAAGCGCTAAAGGGCCTGTACTAGCG 
               
               
                   
               
               
                 TTTCTTACTCTGGTGGGTATAATTAATGCTCTCTACATCAAAAACG 
               
               
                   
               
               
                 Position 2776965..2787971 
               
               
                 SEQ ID 16 
                   
               
               
                 GCCACGAACCTGTAGCCGTTTGGATGAAGCCATATAATACTGGACCAACCGCCGCAAATA 
                   
               
               
                   
               
               
                 AGTAGCCGACACTTTGAGCAAAATCAGGAATACTAATCTACTTTGCCCTTAAAAAATCTT 
               
               
                   
               
               
                 GAGATGATCCATATCTTGTTTTGCCTTCATTACTGTAGTTGGTCATAAGAAGTGCCCTAC 
               
               
                   
               
               
                 ATTCATTAGATTACTTGTCTAATAATTGTAGGGCACTTGGGTTGAGAAAAATGATGTTAA 
               
               
                   
               
               
                 CTAAGAATGCAAACGAACTAAAATCTTTGCTTGCTTTTTATCCTTTTCTAAGGATTCAAT 
               
               
                   
               
               
                 TCCTTCTGAAACTAATTCATTTAATTCAATCTTTTTTGTAATGACCTGTTTGAATAGTGA 
               
               
                   
               
               
                 ACGATGGGTATCTATAATCTTAATTACTCGATCGAAGATATTGGCATATCCATAAGATGT 
               
               
                   
               
               
                 TAATAAACTACCACCTTTTTTAAGAAGAGCTCTAACATCTACAACTGGTGGATGTTGAAA 
               
               
                   
               
               
                 TAATGCAATCACGGTAACCTTGCCACCATTTTTAAGAGCCTGAATGGCACCAGTAAGTGT 
               
               
                   
               
               
                 GGGTTGTACACCGGCGCAATCAAACGCAATATCCACTCCCTGATTTTCCGTGATAGTGCT 
               
               
                   
               
               
                 GATAGCGTGAGCTAATGACTTTTGACTATCAGCACGTATTGGGTATTGAATTCCTAATTC 
               
               
                   
               
               
                 ATTTGCTAAATTCAAACGTTCCTCTGACATGTCATTTATTATGACGTGATGTGCACCAGA 
               
               
                   
               
               
                 AATTTGTGCTATTAAGGCCGTGAACAATCCAATTGGACCAGCACCTTGAATTAAAACATC 
               
               
                   
               
               
                 ATCTCCAGGAGACACTCGGCTTGCCATAACTGCCTGTGCAGCAACTGAAACTGGTTCAAC 
               
               
                   
               
               
                 TAAGGCCCCTAAATCAAGCGGAAAGCTAGCTGGTAAGAGATGTGCAAAGGTACTTTTTAC 
               
               
                   
               
               
                 ATTGCACTTTTCAGCTAAGCCACCGTTAGCCGAAAATCCTAAGAATCCTGCTGATTGATC 
               
               
                   
               
               
                 ACTACCTATAGCATGTTCACACCAATTATAATGACCAGAAAGACATTCCGGACATTTTCC 
               
               
                   
               
               
                 ACAAGCAATCATTGGTTCGACTGCAACTTTATCTCCAATTCTTAATTTAGATACTTGTTT 
               
               
                   
               
               
                 TCCAATTTTAGAAATCGTCCCAGAAAATTCATGACCAGGAATTAGCGGGGCTTGCATATG 
               
               
                   
               
               
                 GGTTAGCGGATGAGGTATTGTCGCCAAATCCATACCCTCTAAATATTCATGAATGTCACT 
               
               
                   
               
               
                 ACCGCAAATACCATTAAATGCAACCTCAATTTGAACTTCATCTGGTGCGGGATCAGGAAT 
               
               
                   
               
               
                 ATTTCTTTTTTCAAAGCGGATATCCTTAGGACCGTAAATAACAGCTGCCTTCACCATAGT 
               
               
                   
               
               
                 CATAGTGCTTCGCTTCCTTCATGTTCAATATAGCACAATCGTATATAAAATAGTGAATAG 
               
               
                   
               
               
                 ATTTCAGTAATGAAGTTACCATCTTGACTTAACAAAAACTTGCTAACTGATTATATGAGA 
               
               
                   
               
               
                 AACTTTTACTTGAAACATTTTTGGTGATTACCATTAATTCCCTCGGACATATTTTGAAAA 
               
               
                   
               
               
                 ACCCTATTTGATGCTGATTGCAAATTATTTTATGCGTATTTATTAAGGGTTTCTATGTTG 
               
               
                   
               
               
                 AAGTATATAGCAAACTTGTTCAAGTAACTGACTTTCACGTGGGCTTTAGCCAAGAGATGC 
               
               
                   
               
               
                 TGAGCAGCGAACCCAAGGGGTGTTACTCGCCCACGCAAAAAAGAAATCCAATTGCATTCC 
               
               
                   
               
               
                 AGTATGAGCGAGAAGCAAGCCATTAAGACGCTGATTCATGAACTCGCGCACAGTGAATTA 
               
               
                   
               
               
                 CATTGTGATCCGAAGTTAAAATTGGATCGTTCAACCATGGAATTGGAAGCTGAAAGTACC 
               
               
                   
               
               
                 GCGTTTATCGTTTGTCAACATTTGGGAATTGACACGAGTGATTATACGTTTCCTTACCTT 
               
               
                   
               
               
                 GCTGTTTGGTCGAAAGATAAGGATCTTTCCCAGCTCTCCAAAAGCTTAACGCGTATCCAA 
               
               
                   
               
               
                 TCCACCGTCGAAAAATTCAATAAAACCGTCGATCAAAACCTTGAAAAGATTCGTGAGAAA 
               
               
                   
               
               
                 CCGTTGACGCTTGATCAAAAAATAGAACGCGCTAAAACCATTGCGACAACGGAAAACATC 
               
               
                   
               
               
                 GCAAAAAAAGAGCAAGGGCTGGTGCAAGCAACGCAGGAGAAAACACGCTAACCCATTTGT 
               
               
                   
               
               
                 TGAATACTCTCACTCAAGAGGACACTCCAGCCCTTGATCACCCAAGAAAGGAATTACCAA 
               
               
                   
               
               
                 CATGAAAACCATTGACGAAATGAACGAATTCGATCGTGACATTATCTTACTTCACCGCAA 
               
               
                   
               
               
                 GTCTGTGAGCGAAGATACACCGCAGGCAATTCTTGTGAAAGTGAAACAGATTCGTAACGC 
               
               
                   
               
               
                 AATTGCCGACGAAAAGGCGGGTAAAGAAGATCCAATTGAGAAAGAATTTACACTCGAATG 
               
               
                   
               
               
                 TTACGACGAAGCAATCAGAAAACTAAGGGACCTTTCGGTCGCTGATTATCAGTTGTGGTT 
               
               
                   
               
               
                 GCGTCAAAACAAAGACCTGGAAGGGTTTGAATTTTGATTTTGAAGGGTGTCGTAGACCCC 
               
               
                   
               
               
                 TTCAAAATAACGGGGGATTGGGGGCGTGCCCCCAAAACAAAATTGACTATCAGCGGAGCT 
               
               
                   
               
               
                 GATATTGGATCAATTTATCGCAAGTGGACGTCCACTTGCAAATCTCGCGACAGTAGAAAA 
               
               
                   
               
               
                 AGCCCCAGAAAAGCAAATCTGAAAAAATGTAACAGGCACTTGATATCAAGTGCCTTATTG 
               
               
                   
               
               
                 TTTCTAGGATCGCTAAAAATAACAGGAGGTGGTTACATGAAGCAATCTGATGAACACCGC 
               
               
                   
               
               
                 ACGCGTTCAGTGAGAAGCACTGTGCGTATGACCCCAGAGGAGCGTGCTTGGGTTGATATG 
               
               
                   
               
               
                 AGAAGAGCCTCTGTCGGCAATCCAAAGTTCAATGCATTTGCCTGTCGCGCACTCACGACG 
               
               
                   
               
               
                 AGCAAGATCGTTCATGTACATTTTACTGATACTAAAAAGTTACTTAGACAGCTGTCAAGA 
               
               
                   
               
               
                 ATTGGGAATAAGGCTCCTATGCTGTAATTACGGACAAAAATAGTTTGTGCGATAATTACA 
               
               
                   
               
               
                 GCATAAGGGCCTCTAGGTCGGAGCCCAGGAGGCGGAGACCGCCGCACAGCCCAACCCCAC 
               
               
                   
               
               
                 GCCGAACCGGAGGCCAGCCCGCCCGCACCGCGGCCGCAATCATCCACCCAACGCCCCCCA 
               
               
                   
               
               
                 AGTTTTTGATAGCGGTAACAACGCCTGTGCGCTTGTCGTGGCCGGCCTTTTTTCATAAGG 
               
               
                   
               
               
                 TTGGAGGAGAAAGGAAGGGTGGTTATGGGCGCTTGGTATGAACACGCAATTATTTACCAA 
               
               
                   
               
               
                 ATCTATCCAAAATCGTTTCAAGACAGCAACGGCGACGGCATCGGGGACCTGAACGGGATC 
               
               
                   
               
               
                 CGGCAACGGATCCCGTACCTGCAAGCCCTCGGCATCAACACGGTGTGGCTGAACCCGATC 
               
               
                   
               
               
                 TTCGTCTCCCCACAGGTGGATAACGGCTACGATGTTGCCAATTACTTCGCCGTGGACGAA 
               
               
                   
               
               
                 ACCATGGGTACGATGGCCGACCTGGAGGCGCTGATCGCGGCTCTGCACGCGGCCGGCATC 
               
               
                   
               
               
                 CGTCTGATCATGGACTTTGTGCTAAACCACACCTCGGATCAGCACCCGTGGTTCCAGGAC 
               
               
                   
               
               
                 GCCATTCACGCCAAAAATAGTCTGTACCGCGACTACTACATTTTCTCTGGCCACGACGGG 
               
               
                   
               
               
                 CAGCTGCCAAACAACTGGGGCAGCTTCTTCGGCGGATCGGTTTGGGCGCCGGATCCGGCG 
               
               
                   
               
               
                 GGAACCGGGCAGTCGTATTTTCATCTGTTCGACCGGCGGATGCCGGATCTGAACTGGGCC 
               
               
                   
               
               
                 AATCCCGAGGTGCGGCGGGCGATGGGAGACGTCGCCACGTTCTGGCTCGGCAAGGGCATC 
               
               
                   
               
               
                 GACGGACTGCGGCTGGATGCCTTCATCCACATTGCCAAGGCCGATCTGGGGCAGGATTAC 
               
               
                   
               
               
                 CCCCTGGCTCCGGGGCAGCAGACGCCGGTGGTGGCGGAGCCGTTTTTCTCCAACCTCCCG 
               
               
                   
               
               
                 AAGGTGCAGGAATGGCTGCGGCCGTTCTGCGACCGGATCAAAACCGACTACCCCGACGCG 
               
               
                   
               
               
                 TTTCTGCTCGGCGAGGCGGCATCGGCCAACGTTAACCTGGCGGCGGATTACACCGCGCCT 
               
               
                   
               
               
                 AGCCAGCACCTGATGGACAGCGTGATCACGTTCCGCTACTTCACCGAGGACGAAAGCGGC 
               
               
                   
               
               
                 CTGGATCCGCGGCTGCCGGCGCAGTACCAGCCGCGGACGCTGGATTTCCCGGCGTTCAAG 
               
               
                   
               
               
                 CAAACCCAGGCGGTGTGGCAGCAGACCCTCGCCGGGGTGTCGATGCCGACGCTGTACTGG 
               
               
                   
               
               
                 GGCAACCACGACATGGCCCGGCTGGCGACGCGGGTGGCCAAAACCACCACCCAGGCGCGC 
               
               
                   
               
               
                 AGTCTGGCCATGCTGATGTACCTGCAGCGCGGCCTGCCGGTGATCTACTATGGCGAGGAG 
               
               
                   
               
               
                 CTCGGGCTACACAACCTGCAGTTCGATCACGTTGATCAGTTTGCGGACGTTTCGGTGGCG 
               
               
                   
               
               
                 CCGTTCGTGGCCGCGGTCGAGGCCACCGGGCAGTCGCGGAGCGCGGCGCTGGCCATGGTG 
               
               
                   
               
               
                 TCGGCGACGCACAAACTGCCGGCACGGGGGCCGATGCCTTGGACGACCGGGTTGCACCAG 
               
               
                   
               
               
                 GGCTTTTCCAATCACCTGCCGTGGCTGGTTGGGCGCAGCGAGGACGTGACCAGCGTGGCC 
               
               
                   
               
               
                 GCGCAGCAGGCCGATGAGGCCAGCATGCTGCACTTCTACCAAGCGCTGATTGCCCTGAAG 
               
               
                   
               
               
                 AAGCAGCCGCTGTTTCAGGCCGGGCATTACCGGCTGCTGACGACGGCGCCGAACCTGTAC 
               
               
                   
               
               
                 GTCTACGAACGCACGCTGGCCAGCCGGCGGGCCCTGGTGGCGGTGGCCTTGGATGAGCAA 
               
               
                   
               
               
                 GGCGCCACCTTCACCGTGCCTGAAGGCCTGACGACCGTGGCGCTGGCCGCCGGCGATTAC 
               
               
                   
               
               
                 CAACTCGAAGGTCAAACGCTCACGCTTGGCGCGAACGCCGGCGTGGTGTTAAACGAAAGG 
               
               
                   
               
               
                 GGAACTCGATAACCATGCAACTTGCAGCATTACGGCACCGCCCAGAAAGCGAAGATTGTT 
               
               
                   
               
               
                 TTTTGTACACTCCAGATGAGCTGCGGCTGCGGCTCCACACAGCCAAGGCCGACGTGCAGG 
               
               
                   
               
               
                 CGGTCATCGTACTGTACGGGGATCCGTATGTCACCGCGCCGAACCCGACCACCGGAGAAC 
               
               
                   
               
               
                 CGGAATTCGCCTACCAAGAGGCGGCGATGATCAAAACCGGCACCGGCCAAACCAGCGACT 
               
               
                   
               
               
                 ACTGGACCATCAGCCTGACCGCGCCTTATCACCGCCTGCAGTACCAGTTCCTGGTGACCG 
               
               
                   
               
               
                 GTCAGGACGGCAACACCGTCCTGCTCGGCGACCGCGGCTTGCGGGCCGACAGCGCCGCCA 
               
               
                   
               
               
                 ACCGCCGGGCCGATCTGTTCCGGGTGCCGTACTTCCACGCCATCGACACGGTACAGACGC 
               
               
                   
               
               
                 CGGCCTGGGTCAAGGAAACCGTGTGGTACCAGATATTCCCGGAACGCTTCGCCAACGGGG 
               
               
                   
               
               
                 ACAAGACGAACGACCCCAAGGGCACCAAGCCTTGGCGTCCGGCGGATCACCCGGGCCGTG 
               
               
                   
               
               
                 AGGATTACTACGGTGGCGACTTGCAAGGGGTGCTGGACCACCTGGACGACCTGCAGGCGC 
               
               
                   
               
               
                 TCGGCGTGAACGGGCTGTACTTCTGCCCGGTGTTCACGGCGATGTCGAATCACAAGTACG 
               
               
                   
               
               
                 ACACCATCGACTACTTCAACATCGACCCTGCGTTTGGCGACAAGGCCTTGTTCGCCGATC 
               
               
                   
               
               
                 TGGTCAACCAAGCGCACCGCCGCGGCATGCGGGTGATGCTGGACGCTGTGTTCAACCACA 
               
               
                   
               
               
                 TGGGCAGCCGCAGCATGCAGTGGCAAGACGTGCTGAAGTTCGGTCCGCAGTCGCGCTTCG 
               
               
                   
               
               
                 CCTCCTGGTTCCACATCAACCGTTTTCCGGCGGCGCCCTTCGCCGCGCCGGAACAGGGCG 
               
               
                   
               
               
                 GCGTGCCGCAGTACGACACCTTCGCCTTCGAACCGCACATGCCGAAGCTCGACACCAGCA 
               
               
                   
               
               
                 ACCCGGCGGTGCAGGACTACCTGCTTGAGGTGGCGACGTACTGGATCAAACAGTTCGACA 
               
               
                   
               
               
                 TCGACGCCTGGCGGCTGGATGTGGCCAACGAGGTGGACCATCACTTCTGGAAACGGTTCA 
               
               
                   
               
               
                 ATCAGGCAACCAAAGCGCTCAAGCCCGATTTCTTCGTGCTGGGCGAGGTCTGGCACTCCA 
               
               
                   
               
               
                 GCCAGCCGTGGCTTAACGGGGATGAGTTCGATGGGGTCATGAACTACGCGTTCACCGAGC 
               
               
                   
               
               
                 AGATCGAGGCCCACTTCCTGACCGGCAAGCTGAGTGCTCCTGAGCTGACGGCGGCGCTGA 
               
               
                   
               
               
                 CGGATCAGCTGATGCTGTACCGCGACCAAACCGACCAGGCGATGCTGAACATGCTGGACT 
               
               
                   
               
               
                 CGCATGACACCGCGCGGCTGCTAACGGTGGCCGGCGGCGACGAGGACCTGGCCCTGCAGG 
               
               
                   
               
               
                 CGCTGGCCTTCACCTTCCTGCAAACCGGGATGCCGTGCCTGTACTATGGCACGGAAATGG 
               
               
                   
               
               
                 GCATGGCCGGAGAAAACGATCCCGACTGCCGGCGGCCAATGGACTGGGCCCAGCTGAAGG 
               
               
                   
               
               
                 GCCCGATTTGGCAGCGTGTGCAGGCCCTTGTGACCTTCCGCCGCGCCCAGTCGGCAACGC 
               
               
                   
               
               
                 TAGGCACCGGCACCACGGCGCTGAGCGTGACCGCAGCCGGGCTGCTTAAGGTAACCCGCA 
               
               
                   
               
               
                 CAGGTGAGCACACCGTGACGGCGTATTTTAACACCACCAAGCAGATGGCGACACTGACCG 
               
               
                   
               
               
                 TCAGTCCATTACTGGCGCAGGGTTACGCCGGCCAGCGGCTGGCGCCAACCGGGTTTGCTG 
               
               
                   
               
               
                 TTATGGTTCAGTAAGATTATGTTAGCGGTAACAGGCAATTTGACCTTTTAAAAGCGTTTT 
               
               
                   
               
               
                 CATATTATCATAATCAAAAGTGTAGAAAAGTTCAGGTGGCGCAATTCACCTCCCGAAAGT 
               
               
                   
               
               
                 GAAGGATGCAAGATGAAACGGATATTTGAAATCGACCCGTGGCTGGTGCAAAGCCACCAA 
               
               
                   
               
               
                 TTGAACCCCAACGAGAAACGCCTGCAGGAAAGCATGACCGCCATCGGCAACGGCTACATG 
               
               
                   
               
               
                 GGTCTGCGCGGTAACTTCGAAGAAGGTTACAGCGGTGATCACCTGCAAGGCACGTACCTC 
               
               
                   
               
               
                 GGCGGCGTCTGGTTCCCAGATAAAACCGTCGTCGGTTGGTGGAAAAACGGCTACCCGGAT 
               
               
                   
               
               
                 TACTTCGGCAAGGCGATCAACGCGCCGAGCTTCATCGGCATGGCGCTCACCGTGAACGGC 
               
               
                   
               
               
                 GAGCGCGTCGATCTGGCCACCAGCGTCTACCGCGATTTCACCCTCACGCTTGACCTGCAC 
               
               
                   
               
               
                 CAGGGCCTGCTGACCCGGAGCTTCGTGTTCGAGGGCAAAAAGGCCACGGTGCGCTTCACC 
               
               
                   
               
               
                 TTCAAGCGTTTCCTCAGCAACGTAATCAAGGAGGCGGCGCTGGTGCAGCTCACCGCCGAA 
               
               
                   
               
               
                 AGCCTTGTCGGACCGGCCGAGCTGACGGTGGCCGCACAGCTCGACGGCAACGTCACGAAC 
               
               
                   
               
               
                 GAGGACAGCAACTACGACGAGCGCTTCTGGGCACCGCAGGGGGAAAACGCCGCGGCAGGC 
               
               
                   
               
               
                 ACCATCCAGCTGCAGACCAAGCCCAACCCGTTCGGGGTCCCGCAGTTCACGGTGCTGCTC 
               
               
                   
               
               
                 AAGCAAAGCCTGCGCCAAGGGGCAACCCTTTTACCCGGCACCGTGACCACCAGCACCGGC 
               
               
                   
               
               
                 CAGCTGACCAGCACGGTCACGCTGCCGCTGGCGCCAAACGTGCCGGTCCAGCTGGAAAAG 
               
               
                   
               
               
                 GACGTCATCGTGGTCACGAGCCGCGACGTCGCCCCTGAGGCCCAGGCCGAAGCGGCCGCG 
               
               
                   
               
               
                 GAGCTGATGACACAGCTGCAGGGCCAAAGCTTTGCGGCCCAGCTGGCGGCACACACCGCC 
               
               
                   
               
               
                 CTGTGGGCCAAGCGCTGGGCCCAAAGCGACGTGGTGATTGAAGGCGACGACGCGGCCCAG 
               
               
                   
               
               
                 CAGGGGATCCGCTTCAACCTCGCCCAGCTGTTCATGACCTATTACGGCGACGATAAGCGG 
               
               
                   
               
               
                 CTCAACGTGGGGCCGAAGGGTTTCACCGGCGAGAAGTACGGCGGGGCGACCTACTGGGAC 
               
               
                   
               
               
                 ACCGAGGCGTACGTGGTGCCGATGTACGTCGCCGCCACCCCTCCGGCCGTGACCCGGGCA 
               
               
                   
               
               
                 CTGCTGCAGTACCGGCACGACCAGCTGCCCGGCGCCTACCACAACGCCCAGCAGCAGGGG 
               
               
                   
               
               
                 CTCAAAGGGGCCTTGTTCCCGATGGTGACCTTCAACGGCATCGAGTGCCACAATGAATGG 
               
               
                   
               
               
                 GAAATCACCTTCGAGGAGCTGCACCGTAACGCAGCGGTCGCCTTCGCGATTTACCAGTAC 
               
               
                   
               
               
                 ACGGCCTACACCGGCGATGAAAGCTACGTCAACCACGACGGCATGGAGGTGCTGGTGGGC 
               
               
                   
               
               
                 ATCAGCCGCTTCTGGGCGGACCGGGTCCACTTCTCCAAGCGCGCCGGCAAGTACATGATC 
               
               
                   
               
               
                 CACGGCGTCACCGGGCCGAACGAGTACGAAAACAACGTCAACAACAACTGGTACACCAAC 
               
               
                   
               
               
                 ACGATGGCCGCCTGGTGCCTGGAGTACACGCTGGCCCGGCTGCCGAAGGCCGATGCCGCC 
               
               
                   
               
               
                 ATTCAGGCCAAGCTGGCCGTGAGCGCCGCCGAGCAGCGCCAGTGGCAGGACATTATCGAC 
               
               
                   
               
               
                 CACATGTACTATCCGGAGGACAAGAAGCTGGGCATCTTCGTCCAGCACGACACCTTCCTG 
               
               
                   
               
               
                 GATAAGGACCTGCGGCCGGCAAGCTCGATTCCGGCCGACCAGCGGCCAATCAACCAGCAC 
               
               
                   
               
               
                 TGGTCCTGGGACCGAATCCTGCGGTCGCCGTTCATCAAGCAGGCGGATGTGCTCCAGGGC 
               
               
                   
               
               
                 CTGTACTTCCTGAACAATCGCTTCACCCGCGAGCAGAAGGAACGCAATTTTGACTTCTAC 
               
               
                   
               
               
                 GAGCCGCTGACGGTGCACGAAAGCTCGCTGAGTGCCTCGATTCACGCGGTGCTGGCCGCC 
               
               
                   
               
               
                 GAGCTCGGTAAGCAGGATAAGGCCGTTGAACTCTATCAGCGTACGGCTCGTCTGGACCTG 
               
               
                   
               
               
                 GACAACTACAACAACGATACGGCAGACGGTCTGCACATCACCTCGATGACCGGCGGCTGG 
               
               
                   
               
               
                 CTGGCTATCGTGCAGGGCTTCGCCGGCATGCGCTACGACCACGATCAGCTGCGGTTCGAT 
               
               
                   
               
               
                 CCGTTCCTGCCGAAGCAGTGGCAGGGTTACCAGTTCCGCATCAACTACCGCGGCCGGGTG 
               
               
                   
               
               
                 ATCCAGGTCGCGGTGGGGAAAACCGTTGCAGTGACCCTGCTGGCCGGCCCGCCGCTGACC 
               
               
                   
               
               
                 GTCATGGTTGCCGGCCAGCCGCAGCATTTGGAGGTGAGCGCGCATGCTTAAAGGATTGCT 
               
               
                   
               
               
                 GTTCGACCTCGACGGCGTCTTGACCGACTCGGCCAAGTTCCACCTGCAGGCCTGGAGCCA 
               
               
                   
               
               
                 GCTGGCCACCCAGCTGGGCATCACCCTGACGCCGGCCGAGCGCGAAGGCCTGCGCGGCCG 
               
               
                   
               
               
                 CTCGCGGCTGGACTCGCTGAACCTGATTTTGGCGGCAGGCGCCCAGGAAGACCGGTTCAG 
               
               
                   
               
               
                 TGCCGCAGAGAAAACGGCGCTAACCGACCAGAAGAACGCGGTGTACCTGAAGCTGATTCA 
               
               
                   
               
               
                 GACGATGACGCCGGTGGACATCCTGCCGGGCATTCCGCAACTGCTGAAGGACGCGCAGGC 
               
               
                   
               
               
                 GGCCGGCCTGAAAATGGCAATCGCCTCGGCGTCGCGGAACGCCCCGACAATTCTTGACCA 
               
               
                   
               
               
                 CCTGGGCCTGGCCGCCAGTTTCGACGCCATCGTCGATCCGGCGACCCTGCACCGCGGCAA 
               
               
                   
               
               
                 GCCCGACCCGGAGATCTACCAGCAGGCGCAAGCGCTGCTGGGGCTCCAGGCCGCCGAGGT 
               
               
                   
               
               
                 GATCGGCTTCGAGGATGCCTCGGCCGGGGTCGCCGCCATCAAAGCGGCCGGTCAGTTCGC 
               
               
                   
               
               
                 GGTTGGCATCGGGGATGCCCGGCTTCTGGCCGCAGCGGATTACCTAGTGAAAGACACGGC 
               
               
                   
               
               
                 GGCCCTGCAGCTGAGCCAGTTGCAAGCGGCGTTCGCCAAAGAAAGTGGGGAGACTAATGG 
               
               
                   
               
               
                 TTGAAATCGACTTGGACCACCTCTACAAGAAGTACGACGACGGCGAGGATTACTCGGTGG 
               
               
                   
               
               
                 TGGACTTCGACCTTCACATCAAGGATAAGGAGTTCATCGTGTTCGTCGGCCCCTCGGGCT 
               
               
                   
               
               
                 GCGGGAAGTCCACCACGCTGCGTATGATTGCGGGGCTGGAGGACATTACCAAAGGCGAGC 
               
               
                   
               
               
                 TGAAAATCGACGATAAGGTGATGAACGACGTGGCCCCCAAGGACCGCAACATCGCCATGG 
               
               
                   
               
               
                 TGTTTCAGAACTACGCCTTGTACCCGCACATGTCAGTGTACGACAACATGGCGTTCGGCC 
               
               
                   
               
               
                 TAAAGCTACGGCACTACAAGAAGGAGGACATCGACAAACGCGTGCAAAACGCGGCGGAGA 
               
               
                   
               
               
                 TCCTCGGCCTGAAGCCGTTTCTCGACCGGAAGCCGGCCGCCTTGTCCGGGGGCCAGCGGC 
               
               
                   
               
               
                 AGCGGGTGGCCTTGGGCCGGGCCATCGTCCGCGACGCCCCAATTTTCCTGATGGATGAGC 
               
               
                   
               
               
                 CGTTGTCGAACCTGGACGCGAAGCTGCGGGTGTCCATGCGGGCGGAAATCGCCAAGCTCC 
               
               
                   
               
               
                 ACCAGCGCCTGAACACCACCACGATTTACGTGACCCACGACCAAACCGAGGCCATGACTA 
               
               
                   
               
               
                 TGGCCGACCGGGTTGTCGTCATGTCCGTTGGCCACGTGCAGCAGATTGGCACCCCGGCCG 
               
               
                   
               
               
                 AGATTTACCAGAACCCGCGGAACCAGTTCGTGGCCGGGTTCATCGGGTCGCCGGCGATGA 
               
               
                   
               
               
                 ACTTCTTCAACATGACCTACCAGGACGGCTTCGTCAGCGACGGCCAAAGCATTCGCCTCA 
               
               
                   
               
               
                 AAGTGCCGGAAGGCCGGGCGAAGATTCTGGACGACCAAGGGTACAACGGCAAGGAAGTCG 
               
               
                   
               
               
                 TGTTCGGCATCCGGCCGGAGGACATCCATTCGGAGGAGGCCTTCCTGGAGACCTGGCCGG 
               
               
                   
               
               
                 ACGCGGTTATCAGCTCAACCGTGTCGGTGTCAGAGCTCCTGGGCGCCACCGAGCAGCTTT 
               
               
                   
               
               
                 ACCTGAAGGCGGATGACACCGAGTACGTTGCCAACGTCAACGCGCGCGACTTCCACAATC 
               
               
                   
               
               
                 CCGGGGATCATGTGAAAATGGGCTTCGACGTCAACAAGGCGCACTTCTTCAACAAGGACA 
               
               
                   
               
               
                 CGACCATGGCCATCGTGGCTAAGCCGATTCCGCTGGAAGGCTGAGGAGGTGAGTGCATGA 
               
               
                   
               
               
                 CCCCATGGTGGCAGCAAGCCGTCATTTACCAGATCTACCCGAAGAGTTTTCAGGACAGCA 
               
               
                   
               
               
                 ACGGGGATGGCATCGGCGATTTGCCGGGGATTACCAGTCGCCTTGATTACCTTAAGCGGC 
               
               
                   
               
               
                 TGGGCGTCGATGCCCTTTGGCTGAGCCCAGTGTATGTGTCGCCCGGCGAGGACAACGGCT 
               
               
                   
               
               
                 ACGACATCGCGGACTACGAGGCCATCGATCCCCAGTTCGGGACGATGGCCGACATGGACG 
               
               
                   
               
               
                 CCTTGATCGCCGCCGCCAAGCAGCGCG 
               
               
                   
               
               
                 Position 2793833..2794809 
               
               
                 SEQ ID 17 
                   
               
               
                 CCCGCGATTTTGGCGTGATTGGCTTCGACGGGGTATTCCTGGACCAGGTGTCCAACCCCA 
                   
               
               
                   
               
               
                 AGCTGACCACGGTGAAGCAGCCCGTGCAGCGCCTCGGCGAACTGCTGGCCCGCATGCTCC 
               
               
                   
               
               
                 TGCAGAAGGTGGCACAGTCCGGCGCCCAACAGGGGGAGCTGCTGGTCGATCCTGAGCTGA 
               
               
                   
               
               
                 TTGCTCGGGACACGACGCGAAAGTAGATCGGATTTCAACTGTCCTTACCGCTATGGTAGG 
               
               
                   
               
               
                 GCCAGTTTTTAGGCTCTATGTCAAATCTAATTCATAGCTAATAGTTGATTTGGCAACGCC 
               
               
                   
               
               
                 TAAGGCGTCAGCCATATCTTGGTAAGTATGATGGCCTTCACTGACCAGTTGAGCTAGCGC 
               
               
                   
               
               
                 ACCACGTTGAAAACGTGATAAAGTAGAAGTACCCAAAGTAATCACTCCTTATAGCTGGTT 
               
               
                   
               
               
                 GGAATTAACTACTCCATTGTAAGAGATTGCTTTGGGCCTTTTTTTATTTTTGTTCGGATT 
               
               
                   
               
               
                 AATTATAGAATTTGTCTAATTAGTTGAAAATTCTTAGGGTTGCCCATATATCTTTTAGTC 
               
               
                   
               
               
                 TGGTCATTAGTTTTTATGTTTGATCTGCTTTTTTCTGATCGCAAACACCCACAACTGCGA 
               
               
                   
               
               
                 GTGAGTCCTTTTTGAAGTCGTTGACTGTCAACAATACATTTATTTCCACATTGACATTGA 
               
               
                   
               
               
                 CAGAGCCAAAGCGCGTTGCCATTAGAACTGCTTCCAAAAAAGCTAATAACTGTGAGTCGC 
               
               
                   
               
               
                 CCAAACGTTTGATTAGCTAAATCGATACGCTTTTGCATACTAATCCTCCCGCTTGATAAG 
               
               
                   
               
               
                 AAGGTACTTAAATAGTTGCTTTCAATTGATCTAATCGCCATTGGCACCATGAAATAAAGG 
               
               
                   
               
               
                 CTAATTCGTCAATCTTTGGAATGCCATAGGTTCTAGCATACGTTAACTTTTGAGTGGTGA 
               
               
                   
               
               
                 GTAGTTGATCATAGGGTTTACTAATAATACCAACCACAAGGATATCGACTTTTTTGTCAA 
               
               
                   
               
               
                 TCCCGTTGACAGGCTTT 
               
               
                   
               
               
                 Position 2967081..2968319 
               
               
                 SEQ ID 18 
                   
               
               
                 AAATACGCAAAAGAACCCGACGAGAGTTAAGTCTCATCGGGTTCTCAGTCGTGGATGAAT 
                   
               
               
                   
               
               
                 TAGAAGCATTGTTAGCTGCATAACCTTCAACATAGGATCAATAGCTGGTTAGATGGTCAT 
               
               
                   
               
               
                 CTCTCAGACTGTTTGCACCAGATCCAGGCAAACGTGTTTATATCCTTGGTCATACTCAGG 
               
               
                   
               
               
                 ATAGATGGGCATTGTGAGTGCAACAGGACTTAGTTGCTTGTATGCTAGGCAATGTTGGCC 
               
               
                   
               
               
                 TTGATACAGAGGATCACTCTGTTTCTGATCTGGATGATAACCTCGTTTTTCCATTTCAGG 
               
               
                   
               
               
                 ACGCTGTCCCAATAATTGTTGCCCTGGGAGTTTGTCGAATTAAGTCTTGGTGCCACAAAC 
               
               
                   
               
               
                 ACACGCTACGGCTTCTTTTCTTGCAAACTGATCTTAGTATTTAGGGCAGTTGCATGATTA 
               
               
                   
               
               
                 CGGAATTGAACCATTTTATAATGAATCGTCTTTTCTATAAGTCTATAGAAAGTGCAGGTA 
               
               
                   
               
               
                 ATGGCATTTTCTCCAGATCGGATTGTCTAATCAATTTAATTGATTTTTTTGGTGTGTTTG 
               
               
                   
               
               
                 ATTATATTGCTTTTGCAAAGGTACAATATACCTTTTCTCTGCTGCCTTGCGAGCAGCGAT 
               
               
                   
               
               
                 GGCATCCTCCATATGAACATATACACGATTTAGGACAAGATGGCCTTGAAAGTACAGCCT 
               
               
                   
               
               
                 TGCGACCCACTTTTGAGCAGTTTTATCCCAACTAACTCCGATAACGCCAGATTTGTTATT 
               
               
                   
               
               
                 GGACCGTTTAAGTGTAGAAGCAACTAAATTTGTTCGATTAATTAGTTGAAAATTCTTGGG 
               
               
                   
               
               
                 ATTGCCCATGTATTTTTTAGTCTGGTTATTAGCTTTTATGTTTGATCTGCTTATTTCTGA 
               
               
                   
               
               
                 TCGCAAACACCCACAACTGCGAGTGAGTCCTTTTTGAAGTCGTTGACTGTCAACGATACA 
               
               
                   
               
               
                 TTTATTTCCACATTGACATTGACAGAGCCAAAGCGCGTTTCCATTAGAACTGCTTCCAAA 
               
               
                   
               
               
                 AAAACTAATGACTGTGAGTCGTCCAAACGTTTGATTGGCCAAATCGATACGCTTTTGCAT 
               
               
                   
               
               
                 ACTAATCTCCCCGTTTGATAAGAAGGTACTTAAAGAGTTGTTTTCAATTGATCTAGTCGC 
               
               
                   
               
               
                 CATTGGCACCATGAAATAAAGGCTAATTCGTCAATCTTTGGAATGCCATAGGTTCTAGCA 
               
               
                   
               
               
                 TACGTTAACTTTTGAGTGGTAAGTAGTTGATCATAGGGTTTGCTAATAATACCAACCACA 
               
               
                   
               
               
                 AGGATATCGACATTTTTGTCAATCCCGTTGACAGGTTTT 
               
            
           
         
       
     
     CITED LITERATURE 
     
         
         Cahenzli, J., Koller, Y., Wyss, M., Geuking, M. B., and McCoy, K. D. (2013). Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell host &amp; microbe 14, 559-570. 
         Chow, J., Tang, H., and Mazmanian, S. K. (2011). Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol 23, 473-480. 
         Hill, D. A., Siracusa, M. C., Abt, M. C., Kim, B. S., Kobuley, D., Kubo, M., Kambayashi, T., Larosa, D. F., Renner, E. D., Orange, J. S., et al. (2012). Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538-546. 
         Hooper, L. V., Littman, D. R., and Macpherson, A. J. (2012). Interactions between the microbiota and the immune system. Science 336, 1268-1273. 
         Iovieno, A., Lambiase, A., Sacchetti, M., Stampachiacchiere, B., Micera, A., and Bonini, S. (2008). Preliminary evidence of the efficacy of probiotic eye-drop treatment in patients with vernal keratoconjunctivitis. Graefes Arch Clin Exp Ophthalmol 246, 435-441. 
         Khoruts, A., Dicksved, J., Jansson, J. K., and Sadowsky, M. J. (2010). Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent  Clostridium difficile -associated diarrhea. J Clin Gastroenterol 44, 354-360. 
         Klaenhammer, T. R., Kleerebezem, M., Kopp, M. V., and Rescigno, M. (2012). The impact of probiotics and prebiotics on the immune system. Nature reviews. Immunology 12, 728-734. 
         Li, M., Wang, B., Zhang, M., Rantalainen, M., Wang, S., Zhou, H., Zhang, Y., Shen, J., Pang, X., Wei, H., et al. (2008). Symbiotic gut microbes modulate human metabolic phenotypes. Proceedings of the National Academy of Sciences of the United States of America 105, 2117-2122. 
         Mileti, E., Matteoli, G., Iliev, I. D., and Rescigno, M. (2009). Comparison of the immunomodulatory properties of three probiotic strains of Lactobacilli using complex culture systems: prediction for in vivo efficacy. PLoS One 4, e7056. 
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