Method for preventing cadaver kidney graft rejection

FIELD: medicine.

SUBSTANCE: recipient of a cadaver kidney graft is examined to compare recipient's and donor's HLA alloepitopes. The alloepitopes found in the donor, but not found in the recipient are recovered. It is followed by comparing the recipient's HLA-DR antigens and the recovered alloepitopes, the derived combinations are compared with the following combinations: A9C-DR7; A10C- DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5. Detecting said combinations enables stating an adequacy of the preventive application of monoclonal antibodies blocking an alpha-chain of an interleukin-2 receptor molecule. The preventive application of the monoclonal antibodies blocking an alpha-chain of the interleukin-2 receptor molecule shall be indicated to the patients with said combinations.

EFFECT: improved outcome of the cadaver kidney grafting that is combined with reducing the price of the method.

1 tbl, 2 ex

 

The invention relates to medicine, namely to transplantation, can be used to prevent transplant rejection cadaveric kidneys.

Kidney transplantation is widely used in the present method of treatment of chronic renal failure. Therapeutic and economic efficiency of this type of treatment is directly dependent on how long a transplanted organ will retain its function.

Every at risk of allograft rejection, leading to loss of function of the transplanted organ. Reason for exclusion lies in genetically determined biological tissue incompatibility recipient and donor, the manifestations of which are recognized by cells of the immune system of the recipient. The primary target of the immune recognition are allogeneic molecules of tissue compatibility (human HLA). The graft is not rejected, if the molecules HLA identical donor HLA molecules of the recipient (Snell, J., The doss J., Natanson C. "tissue", 1976, M.: Mir, s-14).

For the selection of patient matching donor for HLA antigens, required due to high genetic polymorphism of the HLA complex, to search among thousands of potential recipients. This ability is usually absent, and in most cases the patient transplanted organ donor other than the recipient is Tienam HLA (F.H.J. Claas, Roelen L., Dankers M.K.A. et al. "A critical appraisal of HLA matching in today's renal transplantation" / Transplant. Rev., 2004, vol.18, No.2, R-102).

Communication genetically due to tissue incompatibility with graft rejection is complex. On the one hand, the risk of allograft rejection increases with increasing total differences between recipient and donor with HLA antigens (Opelz g, Dohler Century "Effect of human leukocyte antigen compatibility on kidney graft survival: comparative analysis of two decades" / Transplantation, 2007, vol.84, No.2, R-143). On the other hand, the background rejection is incompatible allograft determined by the phenotype of the recipient, for immune alloresponse donor antigens restricitive HLA class II recipient (Abramov VY "Restrizione HLA-DR immune recognition yllapitoon molecules HLA class I transplantation" / In kN.: IV all-Russian Congress of transplant to the memory of academician V.I. Shumakov". / Abstracts / Ed. by Swhite / M, 2008. - P.98-99).

The stimulus that triggers the rejection of the allograft becomes recognition receptors of T lymphocytes of the recipient native of allogeneic HLA molecules of the donor (direct alloresponse) or recognition processioning antigen in complex with the autologous HLA molecule (indirect alloresponse). After receiving additional signals of the T-cell is activated and begins to produce the cytokine is interleukin-2 and to Express the receptor molecules interleukin-2. Binding to the receptor, interleukin-2 provides a signal that triggers a chain of intracellular reactions, culminating in cell division (Helderman J., Goral C. "the Transplant Immunobiology". / In the book. "Guidelines for renal transplantation" / Gamanovich, as amended - Third ed. - Tver: LLC "Publishing house "Triad"", 2004. - P.40-42).

Activation, proliferation and differentiation of T-lymphocytes after transplantation incompatible HLA body can prevent or suppress with drugs - immunosuppressants. Immunosuppressive agents have different mechanism of action. Used drugs that interrupt the transmission of intracellular signals activated, causing dysfunction of the receptor of T lymphocytes that suppress transcription of the gene interleukin-2 or the synthesis of cell nucleotides and other

The increasing application are monoclonal antibodies that block the alpha chain of the receptor molecules interleukin-2. Contacting alpha-chain receptor molecules interleukin-2, they inhibit mediated appropriate cytokine proliferation of activated T-lymphocytes. These antibodies prevent the development of acute transplant rejection, however, does not apply to treatment developed rejection.

The known method using monoclonal antibodies that block the alpha chain of the receptor molecules of interest is lakina-2, the transplantation of cadaveric kidneys, based on double, starting from the day of operation, intravenous recipient allograft blocking the alpha chain of the receptor molecules interleukin-2 monoclonal antibodies in case of simultaneous use of other immunosuppressants (calcineurin inhibitor, corticosteroid hormone inhibitor of the synthesis of nucleotides) (Moisuc AG, Gorbunov V.V., Miloserdov I.A. using a combination of Zenapax and CellCept after a kidney transplant". Manual for doctors. - M.: 2003. - 25 C.). This method is chosen as the prototype.

However, the known method is the prototype has a disadvantage. Despite the fact that blocking the alpha chain of the receptor molecules interleukin-2 antibodies are used to prevent acute transplant rejection due to biological tissue incompatibility of the donor and recipient, using this method does not take into account that acute rejection develops not all recipients, since the possibility of its development is determined by genetic characteristics of the donor and recipient.

We were set a task to develop a simple, efficient, versatile way to prevent acute rejection of the transplant cadaveric kidneys, improves the result of the operation.

The technical result when done is the implementation of the proposed method, is to improve the results of transplantation of cadaveric kidneys by preventing transplant rejection due to adequate immunosuppression, prevent the development of acute transplant rejection, while cheaper way to prevent acute transplant rejection due to the generation of clear indications to the use of a monoclonal antibody that blocks the alpha chain of the receptor molecules interleukin-2.

The invention consists in the following.

The way to prevent transplant rejection cadaveric kidneys includes immunosuppression by assigning inhibitor calcineurin, corticosteroid hormone inhibitor of the synthesis of nucleotides. While previously examined the patient, compare allopatry HLA recipient and donor, identify allopatry present the donor and missing recipient. Compare HLA-DR antigen or antigens of the recipient identified alapitvany. If any of the following combinations: A9C-DR7; A10C-DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5 - complement immunosuppression appointment of a monoclonal antibody that blocks the alpha chain of the receptor molecules interleukin-2.

As a monoclonal antibody that blocks the alpha chain of the receptor molecules interleukin-2, can be used zenapax. When it is introduced within Ivanna dose of 1 mg/kg of body weight within 15 minutes: first, no later than two hours prior to the incorporation of the graft into the bloodstream, then on the 14th day after the operation.

As a monoclonal antibody that blocks the alpha chain of the receptor molecules interleukin-2, can be used simulect, while it is administered intravenously at a dose of 20 mg for 20-30 minutes or bolus: first, no later than two hours prior to the incorporation of the graft into the bloodstream, then on the 4th day after the operation.

Thus, when making decisions about prophylactic use blocking the alpha chain of the receptor molecules interleukin-2 monoclonal antibodies previously examined transplant recipient cadaveric kidneys. Why compare allopatry HLA recipient and donor cadaveric kidneys. Identify allopatry HLA present in the donor, not the recipient. Compare HLA-DR antigens of the recipient identified alapitvany. Then compare the obtained combination with the following combinations: A9C-DR7; A10C-DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5. When identifying these combinations make a judgment about the appropriateness, in addition to the use of calcineurin inhibitor, corticosteroid hormone inhibitor of the synthesis of nucleotides, prophylactic use of blocking the alpha chain of the receptor molecules interleukin-2 monoclonal antibodies. Thus, prophylactic administration of blocking the alpha chain of the receptor molecules interleukin-2 monoclonal is NITEL not be able to show all recipients of cadaveric kidneys, but only with these combinations: A9C-DR7; A10C-DR3; A10C-DR6; AS-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5.

The method is as follows.

Determine HLA-A,B,DR phenotype of the recipient and donor allograft serological or molecular genetic methods.

Investigate HLA-A,B, phenotype of the recipient and donor allograft to determine yllapitoon of HLA molecules using tables allopatry A9, AS, AS, Bw4, B8C, B12C, VS. Consistently verify the identity of each phenotypic identified antigen groups of HLA antigens corresponding to the desired aloepecia. Depending on the facilities antigen HLA determine allopatry HLA, which has investigated the individual.

As table yllapitoon can be used, for example, a table published J.Cecka and E.Reed (J.M. Cecka, E.F. Reed "Histocompatibility testing, cross-matching and allocation of kidney transplants" / In: "Handbook of kidney transplantation. Fourth edition, G.M. Danovitch, ed. - Lippincott, Williams & Wilkins, Philadelphia, 2005. - P.43-71). To identify yllapitoon HLA, we used table 1 (see table 1).

Table 1
Allopatry HLA
ArapitoAntigen HLA
A1CASA2 B17 57 58
ASA10 19 25 26 29 30 31 32 33 34 66 74
A9CA2 9 23 24 28 68 69
A28CA2 28 68 69
B5CB5 18 35 37 51 52 53 58 78
B7CB7 8 13 40 41 42 48 60 61 81
B8CB8 14 16 18 38 39 64 65
B12CB12 13 21 37 40 44 45 47 49 50 60 61
B21CB5 15 17 21 49 50 51 52 53 57 58 62 63 70 71 72 73 75 76 77 78
B22CB7 22 27 42 45 54 55 56 73 81 82
B27CB7 13 27 40 41 42 47 60 61
BW4A9 23 24 25 32 B5 13 16 17 27 37 38 44 47 49 51 52 53 57 58 59 63 77
BW6B7 8 14 18 22 35 39 40 41 42 45 46 47 48 50 54 55 56 60 61 62 64 65 67 70 71 72 73 75 76 78 81

Next, compare allopatry recipient and donor and identify allopatry present in the donor, not the recipient.

Each of these yllapitoon map poacher the bottom with each of the HLA-DR antigens of the recipient.

If the mapping occurs at least one of the following combinations: A9C-DR7; A10C-DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5 - in addition to the application of the inhibitor calcineurin, corticosteroid hormone inhibitor of the synthesis of nucleotides used prophylactically blocking the alpha chain of the receptor molecules interleukin-2 monoclonal antibodies.

In the absence of the following combinations: A9C-DR7; A10C-DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5 - not used prophylactically blocking the alpha chain of the receptor molecules interleukin-2 monoclonal antibodies.

To prove the possibility of implementing the stated purpose in the implementation of our proposed method and achievement of the technical result, the following clinical data.

The proposed method is implemented in the presented examples.

1) Recipient. Patient L-VA, 58 year old woman, And(II). Diagnosis: polycystic kidney disease; chronic renal insufficiency, end-stage, chronic hemodialysis. The phenotype HLA: HLA-A1,3; B14,57(17); DR.1,4. Allopatry: A1C, AS, VS, Bw4, Bw6, VS. The level of preexisting antibodies = 0%.

A donor. Male 30 years, And (II). Diagnosis: severe traumatic brain injury, and death. The phenotype HLA: HLA-A2, B18,40; DR1,11(5). Allopatry: AS, A9, AS, VS, VS, VS, VS, VS, Bw6.

Compared yllapitoon HLA recipient and donor transplant. The donor who attended allopatry AS, A9, AS, VS, VS, VS, VS that are not present in the recipient. Compared these allopatry with HLA-DR phenotype of the recipient. Found that arapito AS generates antigen recipient DR1 combination A28C-DR1.

The patient performed the transplantation of cadaveric kidneys. The length of the primary heat ischemia of the graft 25 minutes Duration of cold ischemia of the graft in the preserving solution "Custodial" 19 o'clock the Function of the transplant immediately. Immunosuppression: cyclosporine-Neoral, mofetil mycophenolate, prednisolone.

Intraoperatively the patient intravenously over 30 min introduced 20 mg blocking the alpha chain of the receptor molecules interleukin-2 monoclonal antibody simulect (basiliximab). Repeated intravenous injection of 20 mg of the indicated antibodies performed at 4 days after surgery. Graft function saves for 6 years.

2) the Recipient. Patient B, male 47 years old, 0(I). Diagnosis: chronic renal failure, end-stage; chronic glomerulonephritis; chronic hemodialysis. The phenotype HLA: HLA-A2; B8,13; DR3,7. Allopatry: AS, A9, AS, VS, VS, Bw4, Bw6, B12C, VS. The level of preexisting antibodies = 10%. Body weight 80 kg

A donor. Male 48 years old, 0(I). Diagnosis: severe traumatic brain injury, and death. The phenotype HLA: HLA-A2,A32; B8,17; DR3.7. Allopatry: AS, A9, AS, A1C, US, VS, WS, WS, WS, Bw6.

Compared allapithato the HLA recipient and donor transplant. The donor was present allopatry A1C, AS, VS that are not present in the recipient. Compared these allopatry with HLA-DR phenotype of the recipient. Found that arapito AS generates antigen recipient DR3 combination A10C-DR3.

The patient underwent transplantation of cadaveric kidneys. The length of the primary heat ischemia of the graft 15 minutes Period of cold ischemia of the graft in the preserving solution "Custodial" 19 o'clock the Function of the transplant immediately. Immunosuppression: cyclosporine-Neoral, mofetil mycophenolate, prednisolone.

Intraoperatively the patient intravenously over 15 minutes entered 80 mg blocking the alpha chain of the receptor molecules interleukin-2 monoclonal antibody zenapax (daclizumab). Repeated intravenous injection of 80 mg of the indicated antibodies performed at 14 days after surgery. The graft retains the function for 2.5 years.

Data retrospective analysis of the results of transplantation of cadaveric kidneys 387 patients with terminal chronic renal failure.

Investigated HLA-A,B, phenotype of all recipients and donor allograft to determine yllapitoon of HLA molecules. Next, map allopatry HLA recipient and donor and revealed allopatry present in the donor, not the recipient. Each of these yllapitoon HLA apostasioideae with each of the HLA-DR antigens of the recipient.

After comparing incompatible yllapitoon HLA donor with HLA-DR antigens of the recipient was found that in the absence of incompatible combinations of allophilia HLA donor and HLA-DR antigen recipient: A9C-DR7; A10C-DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5 was made 249 transplant cadaveric kidneys.

Monoclonal antibodies that block the alpha chain of the receptor molecules interleukin-2, prophylactically in addition to the use of calcineurin inhibitor, a corticosteroid hormone and inhibitor of the synthesis of nucleotides were introduced 29 of 249 specified recipients. One-year allograft survival was these recipients 90%.

Monoclonal antibodies that block the alpha chain of the receptor molecules interleukin-2, prophylactically in addition to the use of calcineurin inhibitor, a corticosteroid hormone and inhibitor of the synthesis of nucleotides was not introduced other 220 of 249 specified recipients. One-year allograft survival was these recipients 89%.

In the presence of at least one of the following combinations of incompatible aloepecia HLA donor and HLA-DR antigen recipient: A9C-DR7; A10C-DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5 - transplantation of cadaveric kidneys was performed in 138 patients.

Monoclonal antibodies that block the alpha chain of the receptor molecules interleukin-2, oseltamivir additional is but to the use of calcineurin inhibitor, corticosteroid hormone and inhibitor of the synthesis of nucleotides were introduced 20 of these 138 recipients. One-year allograft survival was these recipients 90%.

Monoclonal antibodies that block the alpha chain of the receptor molecules interleukin-2, prophylactically in addition to the use of calcineurin inhibitor, a corticosteroid hormone and inhibitor of the synthesis of nucleotides was not introduced to the rest of 118 of these 138 recipients. One-year allograft survival was these recipients 70%.

The above data prove that the proposed method can accurately determine the indications for prophylactic use of a monoclonal antibody that blocks the alpha chain of the receptor molecules interleukin-2, thus improving the results of their operations while cheaper way to prevent acute transplant rejection.

1. The way to prevent transplant rejection cadaveric kidneys, including immunosuppression by assigning inhibitor calcineurin, corticosteroid hormone inhibitor of the synthesis of nucleotides, wherein the pre-survey recipient, with map allopatry HLA recipient and donor, identify allopatry present the donor and missing recipient, sopost the keys HLA-DR antigen or antigens of the recipient identified alapitvany and in the presence of the following combinations: A9C-DR7; A10C-DR3; A10C-DR6; A28C-DR1; Bw4-DR6; B8C-DR3; B12C-DR2; B27C-DR5 - complement immunosuppression appointment of a monoclonal antibody that blocks the alpha chain of the receptor molecules interleukin-2.

2. The method according to claim 1, characterized in that as a monoclonal antibody that blocks the alpha chain of the receptor molecules interleukin-2, use zenapax, while it is administered intravenously at a dose of 1 mg/kg for 15 minutes: first, no later than 2 hours before turning on the transplant into the bloodstream, then on the 14th day after the operation.

3. The method according to claim 1, characterized in that as a monoclonal antibody that blocks the alpha chain of the receptor molecules interleukin-2, use simulect, while it is administered intravenously at a dose of 20 mg for 20-30 minutes or bolus: first, no later than 2 hours before turning on the transplant into the bloodstream, then on the 4th day after surgery.



 

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31 cl, 2 tbl, 114 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula (I), where R represents hydrogen atom or P(=O)(OH)2, X represents oxygen atom or sulphur atom, Y represents CH2CH2 or CH=CH, R1 represents trifluoromethyl, difluoromethyl or cyano, R2 represents alkyl, which has 1-4 carbon atoms, and optionally substituted with hydroxyl group (groups) or halogen atom (atoms), R3 and R4 can be similar or different, and each represents hydrogen atom or alkyl, which has 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid-additive salt. Invention also relates to 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propan-1,3-diol or its hydrochloride and pharmaceutical composition, containing said compounds.

EFFECT: elaboration of pharmaceutical composition, applied for treatment or prevention of autoimmune diseases, prevention or suppression of resistance or acute rejection or chronic rejection of organ or tissue transplant; treatment or prevention of graft-versus-host disease (GvH) resulting from transplantation of bone marrow; or treatment or prevention of allergic diseases.

16 cl, 39 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to stents and bag catheters with improved rapamycin release coating, and also to methods for producing such coatings.

EFFECT: production of stents and bag catheters with improved rapamycin release coating.

10 dwg, 24 ex

FIELD: medicine.

SUBSTANCE: what is disclosed is a DNA plasmid for delivery and expression of an antigen, an epitope, an immunogen, a peptide or a polypeptide under the interest. The DNA plasmid contains a cartridge of kanamycin resistance (KanaR) gene wherein the promoter KanaR is modified. The DNA plasmid shows high expression and stability. There are also described a composition containing such DNA plasmid, and methods for immune system stimulation in an animal and immune response induction in an animal with the use of the composition containing the DNA plasmid.

EFFECT: invention is applicable for producing effective DNA vaccines.

18 cl, 21 dwg, 4 tbl, 2 ex

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