Method and compositions for pain relief

FIELD: medicine.

SUBSTANCE: invention concerns method of pain relief by introduction of pharmaceutical composition containing effective amount of α-adrenergic antagonist and pharmaceutical composition, containing effective amount of the selective α-2A-antagonist.

EFFECT: method provides prolonged relief of chronic pain.

104 cl, 12 dwg, 4 tbl, 7 ex

 

The text descriptions are given in facsimile form.

1. A method of alleviating pain in a subject, comprising the introduction of a specified subject a pharmaceutical composition containing an effective amount α-adrenergic agonist and a pharmaceutical composition containing an effective amount of a selective α-2A antagonist.

2. The method according to claim 1, where the pain is neuropathic pain.

3. The method according to claim 2, where this pain is the pain in diabetic neuropathy.

4. The method according to claim 1, where the pain is visceral pain.

5. The method according to claim 1, where the pain is post-surgical pain.

6. The method according to claim 1, where the pain is the pain of cancer or its treatment.

7. The method according to claim 1, where the pain is the pain of inflammation.

8. The method according to claim 7, where this pain is the pain of arthritis.

9. The method according to claim 7, where this pain is the pain in irritable bowel syndrome.

10. The method according to claim 1, where the pain is a headache.

11. The method according to claim 1, where the specified α-adrenergic the definition agonist is a pan-α -2-agonist.

12. The method according to claim 11, where the specified pan-α-2 agonist is a pan-α-1-pan-α-2-agonist.

13. The method according to claim 1, where the specified α-adrenergic agonist is a compound selected from the group consisting of clonidine, brimonidine), dexamfetamine, norepinephrine, the compounds of formula

the compounds of formula

and all their pharmaceutically acceptable salts, esters, amides, stereoisomers and racemic mixtures.

14. The method according to any one of claims 1, 11, 12 or 13, where the specified selective α-2A antagonist is 4-imidazole or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

15. The method according to 14, where the specified selective α-2A antagonist is a compound of formula

or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

16. The method according to claim 1, where the specified selective α-2A antagonist is a BRL 48962 or its pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture.

17. The method according to claim 1, where the specified selective α-2A antagonist is perifericheskie applicable.

18. The method according to claim 1, where the data α -adrenergic agonist, and the specified selective α-2A antagonist is administered perifericheskie.

19. The method according to claim 1 or 18, where the specified α-adrenergic agonist is administered orally.

20. The method according to claim 1 or 18, where the specified selective α-2A antagonist is administered orally.

21. The method according to claim 1 or 18, where the specified α-adrenergic agonist is administered via subcutaneous Minnesota.

22. The method according to claim 1 or 18, where the specified selective α-2A antagonist is administered via subcutaneous Minnesota.

23. The method according to claim 1, where the specified α-adrenergic agonist and the specified selective α-2A antagonist is administered intermittently or continuously for at least three days.

24. The method according to item 23, where the pain persists in the absence of the specified entity of significant levels α-adrenergic agonist.

25. A method of alleviating pain in a subject, comprising peripheral introduction a specified subject a pharmaceutical composition containing an effective amount α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, to provide peripheral analgesia without concomitant sedative action.

26. The method according A.25, where peripheral analgesia is sufficient for the relief of pain, ENISA least 50% without concomitant sedative action.

27. The method according to p. 25 or 26, where the peripheral analgesia is provided essentially in the absence of hypotensive effects.

28. The method according to p. 25 or 26, where the specified α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor is not thiourea or its derivatives.

29. The method according to p. 25 or 26, where the specified α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is not thiourea or 4-imidazole, or their derivatives.

30. The method according A.25 where the pain is neuropathic pain.

31. The method according to item 30, where pain is a pain in diabetic neuropathy.

32. The method according A.25 where the pain is visceral pain.

33. The method according A.25 where the pain is post-surgical pain.

34. The method according A.25, where this pain is the pain of cancer or its treatment.

35. The method according A.25, where this pain is the pain of inflammation.

36. The method according to p, where this pain is the pain of arthritis.

37. The method according to p, where this pain is the pain in irritable bowel syndrome.

38. The method according A.25 where the pain is grown the th pain.

39. The method according A.25 where specified α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is a α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor.

40. The method according to 39, where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is tion.

41. The method according to p where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is a compound of formula

or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

42. The method according to paragraph 41, where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is (-)-enantiomer of compounds of formula

or its pharmaceutically acceptable salt or ester.

43. The method according to p where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic Retz is ptor, is a compound of formula

or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

44. The method according to 39, where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is imidazolones.

45. The method according to item 44, where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is a compound of formula

or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

46. The method according to item 45, where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is (+)-enantiomer of the compound represented by the formula

or its pharmaceutically acceptable salt or ester.

47. The method according to 39, where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor is a compound selected from the group consisting of

and all pharmaceutically acceptable salts, esters, amides, stereoisomers or racemic mixtures.

48. The method according A.25 where specified α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, administered orally.

49. The method according A.25 where specified α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, administered via subcutaneous Minnesota.

50. The method of selection of effective agents, providing peripheral analgesia without concomitant sedative action, comprising the steps:

(a) interaction α-2A-receptor with α-adrenergic agonist with analgesic activity; and

(b) determine whether the specified agonist α-2A-agonistic activity, where the absence of α-2A-agonistic activity indicates that the specified α-adrenergic agonist with analgesic activity, is an effective agent that provides peripheral analgesia without concomitant sedative action.

51. The method of selection of effective agents, providing peripheral analgesia without Sopot is adequate sedative action, comprising the steps:

(a) interaction α-2A-receptor with the agent;

(b) determine whether the specified agent α-2A-agonistic activity;

(c) interaction α-2V-receptor with the specified agent; and

(d) determine whether the specified agent α-2V-agonistic activity;

where no α-2A-agonistic activity and the presence of α-2V-agonistic activity indicates that the agent is an effective agent that provides peripheral analgesia without concomitant sedative action.

52. The method of selection of effective agents, providing peripheral analgesia without concomitant sedative action, comprising the steps:

(a) peripheral injection α-adrenergic agonist control animal having at least the levels of wild-type activity α-2A-receptor;

(b) analysis of pain in the specified animal control;

(c) peripheral injection of an appropriate experimental animal having reduced levels of expression or activity α-2A-receptor, in the number specified α-adrenergic agonist, of the same or larger than the number entered to the specified control animal; and

(d) analysis of anesthesia at the specified experimental the tal animal, with lower levels of expression or activity α-2A-receptor,

where the lack of pain control in the specified control animal and the presence of pain in the specified experimental animal having reduced levels of expression or activity α-2A-receptor, indicates that this α-adrenergic agonist is over α-2A-agonistic activity; and

where the presence of pain in the specified control animal and the presence of pain in the specified experimental animal having reduced levels of expression or activity α-2A-receptor, indicates that this α-adrenergic agonist is an effective agent that provides peripheral analgesia without concomitant sedative action.

53. The method according to paragraph 52, where the specified control animal is an animal that has both locus α-2A-receptor wild-type.

54. The method according to item 53, where the specified control animal is an animal of the wild type.

55. The method according to item 54, where the specified wild animal is a mouse wild-type.

56. The method according to paragraph 52 or 55, where the specified experimental animal is homozygous point mutation in the locus α-2A-receptor.

57. The method according to p, where the specified experimental animal has a point mutation in the limit of the x coding sequence α -2A-receptor.

58. The method according to 57 where the specified point mutation occurs in the residue, similar Asp79.

59. The method according to 58 where the specified point mutation is a mutation Asp79 on Asn.

60. The method according to paragraph 52 or 55, where the specified experimental animal is homozygous α-2A-knock-out mutation.

61. The method according to paragraph 52 or 55, where steps (b) and (a) analgesia analyze after sensibilization sulprostone.

62. The method according to paragraph 52, further including:

(e) peripheral the introduction of this α-adrenergic agonist experimental animal having reduced levels of expression or activity α-2V-receptor; and

(f) analysis of analgesia in the specified experimental animal having reduced levels of expression or activity α-2B receptors

where the lack of pain control in the specified control animal and the presence of pain in the specified experimental animal having reduced levels of expression or activity α-2A-receptor, indicates that this α-adrenergic agonist is over α-2A-agonistic activity; and

where the presence of pain in the specified control animal, the presence of pain in the specified experimental animal having reduced levels of expression or actively the ti α -2A-receptor, as well as the absence of pain in the specified experimental animal having reduced levels of expression or activity α-2V-receptor, indicates that this α-adrenergic agonist is an effective agent that provides peripheral analgesia without concomitant sedative action.

63. The method of selection of effective agents, providing peripheral analgesia without concomitant sedative action, comprising the steps:

(a) peripheral injection α-adrenergic agonist control animal having at least the levels of wild-type activity α-2V-receptor;

(b) analysis analgesia in a specified control animal;

(c) peripheral injection of the specified α-adrenergic agonist experimental animal having reduced levels of expression or activity α-2V-receptor; and

(d) analysis of analgesia in the specified experimental animal having reduced levels of expression or activity α-2B receptors

where the presence of pain in the specified control animal and the absence of pain control in the specified experimental animal having reduced levels of expression or activity α-2V-receptor, indicates that this α-adrenergic the definition agonist is an effective agent, providing peripheral analgesia without concomitant sedative action.

64. The method according to p, where the specified control animal is an animal that has both locus α-2V-receptor wild-type.

65. The method according to p, where the specified control animal is an animal of the wild type.

66. The method according to p, where the specified wild animal is a mouse wild-type.

67. The method according to p, where the specified experimental animal is heterozygous α-2V-knock-out mutation.

68. The method according to p, where the specified experimental animal is homozygous α-2V-knock-out mutation.

69. The method according to p or 66, where steps (b) and (d) the analgesia analyze after sensibilization sulprostone.

70. The long way of easing chronic pain in a subject, persisting in the absence of continuous activation analgesic α-adrenergic receptor, including the introduction of a specified subject a pharmaceutical composition containing an effective amount α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, or a pharmaceutical composition containing an effective amount α-adrenergic agonist and a pharmaceutical composition containing an effective amount of selecti the nogo α -2A antagonist, for at least three days.

71. The method according to item 70, where chronic pain is maintained, for example, at least three weeks in the absence of the specified subject to significant levels of agonists.

72. The method according to item 70, where the pain is neuropathic pain.

73. The method according to item 72, where this pain is the pain in diabetic neuropathy.

74. The method according to item 70, where the pain is visceral pain.

75. The method according to item 70, where the pain is post-surgical pain.

76. The method according to item 70, where this pain is the pain of cancer or its treatment.

77. The method according to item 70, where this pain is the pain of inflammation.

78. The method according to p, where this pain is the pain of arthritis.

79. The method according to p, where this pain is the pain in irritable bowel syndrome.

80. The method according to item 70, where this pain is a headache.

81. The method according to item 70, where specified α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is α-2V-agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor.

82. The method according to p where specified α-2B agonist with which the Eney than 25% efficiency compared with brimonidina against α -2A-adrenergic receptor, is tion.

83. The method according to p where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is a compound of formula

or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

84. The method according to p where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is (-)-enantiomer of compounds of formula

or its pharmaceutically acceptable salt or ester.

85. The method according to p where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is a compound of formula

or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

86. The method according to p where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is imidazolones.

87. The method according to p where specified α-2B agonist with less than 25% efficiency the efficiency compared to brimonidina against α -2A-adrenergic receptor, is a compound of formula

or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

88. The method according to p where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, is (+)-enantiomer of compounds of formula

or its pharmaceutically acceptable salt or ester.

89. The method according to p where specified α-2B agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor is a compound selected from the group consisting of

and all pharmaceutically acceptable salts, esters, amides, stereoisomers or racemic mixtures.

90. The method according to item 70, where specified α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, enter perifericheskie.

91. The method according to p where specified α-adrenergic agonist, ilusiones than 25% efficiency compared with brimonidina against α -2A-adrenergic receptor, administered orally.

92. The method according to p where specified α-adrenergic agonist with less than 25% efficiency compared with brimonidina against α-2A-adrenergic receptor, administered via subcutaneous Minnesota.

93. The method according to item 70, where specified α-adrenergic agonist is a pan-α-2-agonist.

94. The method according to p where the specified pan-α-2 agonist is a pan-α-1-pan-α-2-agonist.

95. The method according to item 70, where specified α-adrenergic agonist is a compound selected from the group consisting of clonidine, brimonidine), dexamfetamine, norepinephrine, the compounds of formula

the compounds of formula

and all their pharmaceutically acceptable salts, esters, amides, stereoisomers and racemic mixtures.

96. The method according to PP, 93, 94 or 95, where the specified selective α-2A antagonist is 4-imidazole or its pharmaceutically acceptable salt, ester, amidon, stereoisomer or racemic mixture.

97. The method according to p where the specified selective α-2A antagonist is a compound of formula

or its pharmaceutically acceptable salt, ester, amidon, stereos the mayor or racemic mixture.

98. The method according to PP, 93, 94 or 95, where the specified selective α-2A antagonist is a BRL 48962 or its pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture.

99. The method according to PP, 93, 94 or 95, where the specified selective α-2A antagonist is perifericheskie applicable.

100. The method according to item 70, where specified α-adrenergic agonist and the specified selective α-2A antagonist is administered perifericheskie.

101. The method according to item 70 or 100, where specified α-adrenergic agonist is administered orally.

102. The method according to item 70 or 100, where specified α-2A antagonist is administered orally.

103. The method according to item 70 or 100, where specified α-adrenergic agonist is administered via subcutaneous Minnesota.

104. The method according to item 70 or 100, where the specified selective α-2A antagonist is administered via subcutaneous Minnesota.



 

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Asaindoles // 2326880

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51 cl, 9 tbl, 148 ex

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12 cl, 5 ex, 2 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: compositions under this invention are used as treatment or prevention agents for immune diseases including not steroid immunophylin-dependent immunosuppressant (NsIDI) and intensifier NsIDI (NsIDIE), chosen of selective serotonin recapture inhibitor (SSRI), tricyclic antidepressant (TCA), phenoxy phenol, antihistaminic agent, phenothiazine or mu-opioid receptor antagonist.

EFFECT: increased efficiency of immune disease treatment.

38 cl, 26 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: offered means is applied for anaemia prevention and treatment within neurotic states. Such is adrenoceptor antagonists application. It is proved, that introduced adrenoceptor antagonists dihydroergo-thamin or propranolol for narcolepsy depivation provide cancellation of bone-marrow erythropoiesis depression and normalise erythroid blood content.

EFFECT: means has improved efficiency.

5 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmacological formulation used for prevention and treatment of diabetes, containing at least one agent stimulating insulin secretion and at least one inhibitor of FBP-ase, selected of composition formulations I and IA .

EFFECT: improved therapeutic efficiency.

142 cl, 2 dwg, 21 tbl, 15 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns medicinal agent reducing cholesterol content in blood serum or medicinal agent for prevention and treatment of atherosclerosis consisting of combined compound of general formula 1 and inhibitors of cholesterol biosynthesis, medicinal set including this agent, and method of cholesterol reduction in blood serum or prevention and treatment of atherosclerosis.

EFFECT: effective cholesterol reduction in blood serum or prevention and effective treatment of atherosclerosis.

13 cl, 14 tbl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmacological composition for treatment of tumours containing derivative of acryloyldistamicine of formula (1) and inhibitor of protein kinase, product containing derivative of acryloyldistamicine of formula (1) and inhibitor of protein kinase, applied derivative of acryloyldistamicine of formula (1) and inhibitor of protein kinase within combined therapy for tumour treatment, as well as method of tumour treatment.

EFFECT: high efficiency of treatment.

27 cl, 4 tbl, 3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to medicinal agents containing combined inhibitor of dipeptidylpeptidase IV (DPPIV) and biguanide agent. Offered application of pharmaceutical agent implies production of preventive and therapeutic agent and method of intensified effects of active circulating GLP-1 and/or active circulating GLP-2. Besides, invention concerns method of prevention or treatment of disease connected with active circulating GLP-1 and/or active circulating GLP-2, specifically diabetes, obesity, hyperlipidemia, gastrointestinal diseases. Combined inhibitor DPPIV of formula (I) and biguanide agent, specifically phenformine, methformin or buformine stimulates action of active circulating glucagon-like peptide-1 (GLP-1) and/or active circulating glucagon-like peptide -2 (GLP-2) and, therefore inhibits destruction of GLP-1 and GLP-2, with their levels raised up with biguanide agent.

EFFECT: agent has improved efficiency.

17 cl, 12 tbl, 425 ex

FIELD: medicine; pharmacology.

SUBSTANCE: composition is intended for treatment or prevention of insulin resistance of susceptible warm-blooded animals, including humans, and contains selective modulator of estrogen receptor EM-652-HC1, taken in amount determined by therapeutic efficiency.

EFFECT: effective treatment of prevention of insulin resistance development for warm-blooded mammals.

5 cl, 20 ex, 12 tbl, 8 dwg

FIELD: medicine; pharmaceutical.

SUBSTANCE: invention refers to pharmaceutical formulation and therapeutic method including introduction to related patient of composition 2-alkyliden derivative of 19-nor-vitamin D and bisphosphonate. In particular, this invention refers to pharmaceutical formulation and therapeutic methods including introduction to related patient of 2-methylene-19-nor-20(S)-1α,25- dihydroxyvitamin D3 and bisphosphonate selected from tyludronate, alendronate, zoledronate, ibanedronate, risedronate, ethydronate, clodronate or pamydronate. Stated invention allows increasing of therapeutic efficiency of such diseases as senile osteoporosis, postclimacteric osteoporosis, bone fracture, bone graft, osteopeny and male osteoporosis.

EFFECT: increased therapeutic efficiency.

18 cl, 2 ex, 2 tbl

FIELD: medicine; pharmacy.

SUBSTANCE: first version implies that pharmaceutical formulation contains antibiotic and prebiotic - oligosaccharide selected from: fructooligosaccharides, galactooligosaccharides, xylooligosaccharides, maltooligosaccharides and isomaltooligosaccharides by degree of polymerization from 2 to 10, and particles sizes up to 0.3 mm and purity not less than 95%, and antibiotic with particles sizes from 20 to 200 mcm; antibiotic and oligosaccharide are included in mass proportion from 1:1 to 1:100 respectively. Second version implies that pharmaceutical formulation contains powder antibiotic with particles from 20 to 200 mcm selected from: beta-lactamase, including combinations of beta-lactams and bacterial beta-lactamases inhibitors; azalides, fluoroquinolones, amphenicoles, glycopeptides, ansamicynes, nitrofurans, phosphonic acid derivatives, cycloserine, trimetoprym, and as a prebiotic - powder oligosaccharide by degree of polymerization from 2 to 10, particles sizes up to 0.3 mm and purity not less than 95%; antibiotic and oligosaccharide are included in mass proportion from 1:1 to 1:100 respectively; mentioned compositions are intended for oral introduction and applied for bowel disbios prevention caused by antibiotic therapy.

EFFECT: stimulates lactobacilli and bifidus bacteria action.

4 cl, 9 ex

FIELD: medicine.

SUBSTANCE: chewing tablet contains the following components: (a) vitamin mixture containing in single dose 0.4 to 0.8 mg β-carotene, 500-1500 IU vitamin A palmitate, 0.3 to 1.0 mg vitamin B1 nitrate, 0.3 to 1.0 mg vitamin B2, 0.3 to 1.0 mg vitamin B6 hydrochloride, 0.4 to 1.0 mcg vitamin B12, 15 to 40 mg vitamin C, 100-300 IU vitamin D3, 3.0 to 9.5 mg vitamin E acetate, 20 to 80 mcg folic acid, 10 to 25 mcg vitamin H and 4 to 10 mg vitamin PP; (b) the mixture of mineral substances containing in single dose 0.2 to 0.8 mg copper carbonate(II), 150 to 300 mg anhydrous dicalcium phosphate, 8.0 to 20 mg iron fumarate(II), 4 to 9 mg zinc oxide and 12 to 28 mg magnesium oxide; (c) containing in single dose 10 to 100 mg (L)-lysine monohydrochloride; (d) at least one sweetener and one or more flavor additive, to mask the unpleasant taste of lysine., (e) and the pharmaceutically or dietetically acceptable carrier, and the tablet is prepared by mixing the different components from (a) to (e) with following pelleting by direct pressing.

EFFECT: invented composition enables preparation of tablet with maximally masked unpleasant taste of lysine by use of simple technique of direct pressing.

5 cl, 2 exr

FIELD: chemistry.

SUBSTANCE: compounds with the formula are described and its pharmaceutically acceptable salts, where Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, m, n, p and q are as specified in the invention. The obtained compounds have the modulating activity regarding the 5-HT receptors. The pharmaceutical composition which contains the compounds with formula (I) and used in treatment of certain central nervous system diseases is also described.

EFFECT: novel compound group with useful biological properties is obtained.

10 cl, 2 dwg, 7 ex

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