Effectiveness of metformin in combination with intranasal insulin for the treatment of metabolic and hormonal disturbances in adult male rats with metabolic syndrome induced by impaired breastfeeding

Kira V. Derkach , Alexander O Ivantsov , Nataliia E Basova , Alexander O Shpakov

Reviews on Clinical Pharmacology and Drug Therapy ›› 2024, Vol. 22 ›› Issue (3) : 289 -300.

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Reviews on Clinical Pharmacology and Drug Therapy ›› 2024, Vol. 22 ›› Issue (3) : 289 -300. DOI: 10.17816/RCF626249
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Effectiveness of metformin in combination with intranasal insulin for the treatment of metabolic and hormonal disturbances in adult male rats with metabolic syndrome induced by impaired breastfeeding

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Abstract

BACKGROUND: Limiting or temporally stopping breastfeeding can lead to the development of metabolic syndrome in adulthood, which requires the development of approaches for its prevention and correction. One such approach is treatment with metformin or intranasal insulin. Since the targets of these agents differ and may complement each other, it has been suggested that their combined use could be effective.

AIM: To study the effect of a four-week co-administration of metformin (orally, 120 mg/kg/day) and intranasal insulin (1.2 IU/kg/day) in male rats with metabolic syndrome, induced by breastfeeding disruption on postnatal days 19–21, on their metabolic and hormonal parameters.

MATERIALS AND METHODS: The study treatment was compared with monotherapy using the same drugs.

RESULTS: It was found that adult male rats with disrupted breastfeeding developed obesity, dyslipidemia, hyperleptinemia, impaired glucose tolerance, and a reduction in the number of β-cells and the area of pancreatic islets, which are characteristic of metabolic syndrome. Long-term treatment with metformin and its combination with intranasal insulin partially or fully normalized body weight, abdominal fat, and metabolic and hormonal parameters, with the restorative effect of combination treatment on such parameters as body weight, fat mass, glucose tolerance, and blood glycated hemoglobin levels being more pronounced than with metformin alone.

CONCLUSIONS: The results of the study support the use of a combination of metformin and intranasal insulin to normalize metabolic and hormonal parameters in metabolic syndrome induced by breastfeeding disruption in early days of life.

Keywords

metformin / intranasal insulin / metabolic syndrome / hyperleptinemia / glucose tolerance / breastfeeding

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Kira V. Derkach, Alexander O Ivantsov, Nataliia E Basova, Alexander O Shpakov. Effectiveness of metformin in combination with intranasal insulin for the treatment of metabolic and hormonal disturbances in adult male rats with metabolic syndrome induced by impaired breastfeeding. Reviews on Clinical Pharmacology and Drug Therapy, 2024, 22(3): 289-300 DOI:10.17816/RCF626249

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References

[1]

de Silva Lima N, de Moura EG, Fonseca Passos MC, et al. Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. Br J Nutr. 2011;105(9):1405–1413. doi: 10.1017/S0007114510005064

[2]

De Silva Lima N., de Moura E.G., Fonseca Passos M.C., et al. Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring // Br J Nutr. 2011. Vol. 105, N 9. P. 1405-1413. doi: 10.1017/S0007114510005064

[3]

Francisco FA, Barella LF, de Silva Silveira S, et al. Methylglyoxal treatment in lactating mothers leads to type 2 diabetes phenotype in male rat offspring at adulthood. Eur J Nutr. 2018;57(2):477–486. doi: 10.1007/s00394-016-1330-x

[4]

Francisco F.A., Barella L.F., de Silva Silveira S., et al. Methylglyoxal treatment in lactating mothers leads to type 2 diabetes phenotype in male rat offspring at adulthood // Eur J Nutr. 2018. Vol. 57, N 2. P. 477–486. doi: 10.1007/s00394-016-1330-x

[5]

Derkach KV, Bondareva VM, Sharova TS, Shpakov AO. Efficacy of various metformin doses for the restoration of metabolic indices and hormonal status in early weaned male rats. J Evol Biochem Physiol. 2022;58(4):1251–1261. doi: 10.1134/S0022093022040275

[6]

Derkach K.V., Bondareva V.M., Sharova T.S., Shpakov A.O. Efficacy of various metformin doses for the restoration of metabolic indices and hormonal status in early weaned male rats // J Evol Biochem Physiol. 2022. Vol. 58, N 4. P. 1251–1261. doi: 10.1134/S0022093022040275

[7]

Derkach KV, Bondareva VM, Shpakov AO. Influence of intranasally administered insulin on metabolic and hormonal parameters in adult male rats, impaired due to three-day fasting in the early postnatal period. Biomeditsinskaya khimiya. 2022;68(4):263–271. EDN: SSXUSF doi: 10.18097/PBMC20226804263

[8]

Деркач К.В., Бондарева В.М., Шпаков А.О. Влияние интраназально вводимого инсулина на метаболические и гормональные показатели у взрослых самцов крыс, нарушенные вследствие трехдневного голодания в раннем постнатальном периоде // Биомедицинская химия. 2022. Т. 68, № 4. C. 263–271. EDN: SSXUSF doi: 10.18097/PBMC20226804263

[9]

Guo Z, Priefer R. Current progress in pharmacogenomics of type 2 diabetes: A systemic overview. Diabetes Metab Syndr. 2021;15(5):102239. doi: 10.1016/j.dsx.2021.102239

[10]

Guo Z., Priefer R. Current progress in pharmacogenomics of type 2 diabetes: A systemic overview // Diabetes Metab Syndr. 2021. Vol. 15, N 5. ID 102239. doi: 10.1016/j.dsx.2021.102239

[11]

Cwynar-Zając Ł. Metformin — a new approach. Pediatr Endocrinol Diabetes Metab. 2021;27(2):134–140. doi: 10.5114/pedm.2021.107166

[12]

Cwynar-Zając Ł. Metformin — a new approach // Pediatr Endocrinol Diabetes Metab. 2021. Vol. 27, N 2. P. 134–140. doi: 10.5114/pedm.2021.107166

[13]

Kononova YA, Likhonosov NP, Babenko AY. Metformin: expanding the scope of application-starting earlier than yesterday, canceling later. Int J Mol Sci. 2022;23(4):2363. doi: 10.3390/ijms23042363

[14]

Kononova Y.A., Likhonosov N.P., Babenko A.Y. Metformin: expanding the scope of application-starting earlier than yesterday, canceling later // Int J Mol Sci. 2022. Vol. 23, N 4. ID 2363. doi: 10.3390/ijms23042363

[15]

Kanto K, Ito H, Noso S, et al. Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2017;9(3):587–593. doi: 10.1111/jdi.12755

[16]

Kanto K., Ito H., Noso S., et al. Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus // J Diabetes Investig. 2017. Vol. 9, N 3. P. 587–593. doi: 10.1111/jdi.12755

[17]

DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. 2016;65(2):20–29. doi: 10.1016/j.metabol.2015.10.014

[18]

DeFronzo R., Fleming G.A., Chen K., Bicsak T.A. Metformin-associated lactic acidosis: Current perspectives on causes and risk // Metabolism. 2016. Vol. 65, N 2. P. 20–29. doi: 10.1016/j.metabol.2015.10.014

[19]

Derkach KV, Bondareva VM, Basova NE, et al. Combined use of metformin and intranasal insulin normalise glucose sensitivity and hormonal status in rats with type 2 diabetes. Integrative Physiology. 2021;2(4): 399–411. EDN: ZFDWAJ doi: 10.33910/2687-1270-2021-2-4-399-411

[20]

Деркач К.В., Бондарева В.М., Басова Н.Е., и др. Совместное применение метформина и интраназального инсулина нормализует чувствительность к глюкозе и гормональный статус у крыс с диабетом 2 типа // Интегративная физиология. 2021. Т. 2, № 4. С. 399–411. EDN: ZFDWAJ doi: 10.33910/2687-1270-2021-2-4-399-411

[21]

Afolabi SO, Folahan J, Agede O, Olorundare O. combined intranasal insulin/saxagliptin/metformin therapies ameliorate the effect of combined oral contraceptive- (COC-) induced metabolic syndrome (MetS) with a major target on glucose metabolism in adult female wistar rats. Int J Reprod Med. 2021;2021:9693171. doi: 10.1155/2021/9693171

[22]

Afolabi S.O., Folahan J., Agede O., Olorundare O. combined intranasal insulin/saxagliptin/metformin therapies ameliorate the effect of combined oral contraceptive- (COC-) induced metabolic syndrome (MetS) with a major target on glucose metabolism in adult female wistar rats // Int J Reprod Med. 2021. Vol. 2021. ID 9693171. doi: 10.1155/2021/9693171

[23]

Oche J, Olorundare O, Afolabi S, et al. Comparative therapeutic effect of single/combined administration of saxagliptin, metformin and intranasal insulin on dexamethasone induced insulin resistance in albino wistar rat model. Niger J Physiol Sci. 2023;38(1):37–46. doi: 10.54548/njps.v38i1.7

[24]

Oche J., Olorundare O., Afolabi S., et al. Comparative therapeutic effect of single/combined administration of saxagliptin, metformin and intranasal insulin on dexamethasone induced insulin resistance in albino wistar rat model // Niger J Physiol Sci. 2023. Vol. 38, N 1. P. 37–46. doi: 10.54548/njps.v38i1.7

[25]

Derkach KV, Bogush IV, Berstein LM, Shpakov AO. The influence of intranasal insulin on hypothalamic-pituitary-thyroid axis in normal and diabetic rats. Horm Metab Res. 2015;47(12):916–924. doi: 10.1055/s-0035-1547236

[26]

Derkach K.V., Bogush I.V., Berstein L.M., Shpakov A.O. The influence of intranasal insulin on hypothalamic-pituitary-thyroid axis in normal and diabetic rats // Horm Metab Res. 2015. Vol. 47, N 12. P. 916–924. doi: 10.1055/s-0035-1547236

[27]

da Lima NS, Franco JG, Peixoto-Silva N, et al. Ilex paraguariensis (yerba mate) improves endocrine and metabolic disorders in obese rats primed by early weaning. Eur J Nutr. 2014;53(1):73–82. doi: 10.1007/s00394-013-0500-3

[28]

da Lima N.S., Franco J.G., Peixoto-Silva N., et al. Ilex paraguariensis (yerba mate) improves endocrine and metabolic disorders in obese rats primed by early weaning // Eur J Nutr. 2014. Vol. 53, N 1. P. 73–82. doi: 10.1007/s00394-013-0500-3

[29]

Pietrobon CB, Miranda RA, Bertasso IM, et al. Early weaning induces short- and long-term effects on pancreatic islets in Wistar rats of both sexes. J Physiol. 2020;598(3):489–502. doi: 10.1113/JP278833

[30]

Pietrobon C.B., Miranda R.A., Bertasso I.M., et al., Early weaning induces short- and long-term effects on pancreatic islets in Wistar rats of both sexes // J Physiol. 2020. Vol. 598, N 3. P. 489–502. doi: 10.1113/JP278833

[31]

Tulipano G. Integrated or independent actions of metformin in target tissues underlying its current use and new possible applications in the endocrine and metabolic disorder area. Int J Mol Sci. 2021;22(23):13068. doi: 10.3390/ijms222313068

[32]

Tulipano G. Integrated or independent actions of metformin in target tissues underlying its current use and new possible applications in the endocrine and metabolic disorder area // Int J Mol Sci. 2021. Vol. 22, N 23. ID 13068. doi: 10.3390/ijms222313068

[33]

Nabrdalik K, Skonieczna-Żydecka K, Irlik K, et al. Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: A systematic review, meta-analysis and meta-regression of randomized controlled trials. Front Endocrinol (Lausanne). 2022;13:975912. doi:10.3389/fendo.2022.975912

[34]

Nabrdalik K., Skonieczna-Żydecka K., Irlik K., et al. Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: A systematic review, meta-analysis and meta-regression of randomized controlled trials // Front Endocrinol (Lausanne). 2022. Vol. 13. ID 975912. doi: 10.3389/fendo.2022.975912

[35]

Shpakov AO, Zorina II, Derkach KV. Hot spots for the use of intranasal insulin: cerebral ischemia, brain injury, diabetes mellitus, endocrine disorders and postoperative delirium. Int J Mol Sci. 2023;24(4):3278. doi: 10.3390/ijms24043278

[36]

Shpakov A.O., Zorina I.I., Derkach K.V. Hot spots for the use of intranasal insulin: cerebral ischemia, brain injury, diabetes mellitus, endocrine disorders and postoperative delirium // Int J Mol Sci. 2023. Vol. 24, N 4. ID 3278. doi: 10.3390/ijms24043278

[37]

Blázquez E, Velázquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol (Lausanne). 2014;5:161. doi: 10.3389/fendo.2014.00161

[38]

Blázquez E., Velázquez E., Hurtado-Carneiro V., Ruiz-Albu¬sac J.M. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease // Front Endocrinol (Lausanne). 2014. Vol. 5. ID 161. doi: 10.3389/fendo.2014.00161

[39]

Mei M, Liu M, Mei Y, et al. Sphingolipid metabolism in brain insulin resistance and neurological diseases. Front Endocrinol (Lausanne). 2023;14:1243132. doi: 10.3389/fendo.2023.1243132

[40]

Mei M., Liu M., Mei Y., et al. Sphingolipid metabolism in brain insulin resistance and neurological diseases // Front Endocrinol (Lausanne). 2023. Vol. 14. ID 1243132. doi: 10.3389/fendo.2023.1243132

[41]

Sharma M, Yadav Y, Dey CS. Neuronal insulin signaling and resistance: a balancing act of kinases and phosphatases. J Endocrinol. 2023;260(1):e230151. doi: 10.1530/JOE-23-0151

[42]

Sharma M., Yadav Y., Dey C.S. Neuronal insulin signaling and resistance: a balancing act of kinases and phosphatases // J Endocrinol. 2023. Vol. 260, N 1. ID e230151. doi: 10.1530/JOE-23-0151

[43]

Bogush M, Heldt NA, Persidsky Y. Blood brain barrier injury in diabetes: unrecognized effects on brain and cognition. J Neuroimmune Pharmacol. 2017;12(4):593–601. doi: 10.1007/s11481-017-9752-7

[44]

Bogush M., Heldt N.A., Persidsky Y. Blood brain barrier injury in diabetes: unrecognized effects on brain and cognition // J Neuroimmune Pharmacol. 2017. Vol. 12, N 4. P. 593–601. doi: 10.1007/s11481-017-9752-7

[45]

Rotermund C, Machetanz G, Fitzgerald JC. The therapeutic potential of metformin in neurodegenerative diseases. Front Endocrinol (Lausanne). 2018;9:400. doi: 10.3389/fendo.2018.00400

[46]

Rotermund C., Machetanz G., Fitzgerald J.C. The therapeutic potential of metformin in neurodegenerative diseases // Front Endocrinol (Lausanne). 2018. Vol. 9. ID 400. doi: 10.3389/fendo.2018.00400

[47]

Madhu LN, Kodali M, Shetty AK. Promise of metformin for preventing age-related cognitive dysfunction. Neural Regen Res. 2022;17(3):503–507. doi: 10.4103/1673-5374.320971

[48]

Madhu L.N., Kodali M., Shetty A.K. Promise of metformin for preventing age-related cognitive dysfunction // Neural Regen Res. 2022. Vol. 17, N 3. P. 503–507. doi: 10.4103/1673-5374.320971

[49]

Abosharaf HA, Elsonbaty Y, Tousson E, Mohamed T. Alzheimer’s disease-related brain insulin resistance and the prospective therapeutic impact of metformin. J Neuroendocrinol. 2024;36(1):e13356. doi: 10.1111/jne.13356

[50]

Abosharaf H.A., Elsonbaty Y., Tousson E., Mohamed T. Alzheimer’s disease-related brain insulin resistance and the prospective therapeutic impact of metformin // J Neuroendocrinol. 2024. Vol. 36, N 1. ID e13356. doi: 10.1111/jne.13356

[51]

Slouha E, Ibrahim F, Rezazadah A, et al. Anti-diabetics and the prevention of dementia: A systematic review. Cureus. 2023;15(11): e49515. doi: 10.7759/cureus.49515

[52]

Slouha E., Ibrahim F., Rezazadah A., et al. Anti-diabetics and the prevention of dementia: A systematic review // Cureus. 2023. Vol. 15, N 11. ID e49515. doi: 10.7759/cureus.49515

[53]

Kaneto H, Kimura T, Obata A, et al. Multifaceted mechanisms of action of metformin which have been unraveled one after another in the long history. Int J Mol Sci. 2021;22(5):2596. doi: 10.3390/ijms22052596

[54]

Kaneto H., Kimura T., Obata A., et al. Multifaceted mechanisms of action of metformin which have been unraveled one after another in the long history // Int J Mol Sci. 2021. Vol. 22, N 5. ID 2596. doi: 10.3390/ijms22052596

[55]

Ismaiel AAK, Espinosa-Oliva AM, Santiago M, et al. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases MPTP-induced damage to the nigrostriatal dopaminergic system. Toxicol Appl Pharmacol. 2016;298:19–30. doi: 10.1016/j.taap.2016.03.004

[56]

Ismaiel A.A.K., Espinosa-Oliva A.M., Santiago M., et al. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases MPTP-induced damage to the nigrostriatal dopaminergic system // Toxicol Appl Pharmacol. 2016. Vol. 298. P. 19–30. doi: 10.1016/j.taap.2016.03.004

[57]

Oliveira WH, Nunes AK, Rocha França ME, et al. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice. Brain Res. 2016;1644:149–160. doi: 10.1016/j.brainres.2016.05.013

[58]

Oliveira W.H., Nunes A.K., Rocha França M.E., et al. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice // Brain Res. 2016. Vol. 1644. P. 149–160. doi: 10.1016/j.brainres.2016.05.013

[59]

Ponce-Lopez T, González Álvarez Tostado JA, Dias F, Montiel Maltez KH. metformin prevents NDEA-induced memory impairments associated with attenuating beta-amyloid, tumor necrosis factor-alpha, and interleukin-6 levels in the hippocampus of rats. Biomolecules. 2023;13(9):1289. doi:10.3390/biom13091289

[60]

Ponce-Lopez T., González Álvarez Tostado J.A., Dias F., Montiel Maltez K.H. metformin prevents NDEA-induced memory impairments associated with attenuating beta-amyloid, tumor necrosis factor-alpha, and interleukin-6 levels in the hippocampus of rats // Biomolecules. 2023. Vol. 13, N 9. ID 1289. doi: 10.3390/biom13091289

[61]

Dludla PV, Nyambuya TM, Johnson R, et al. Metformin and heart failure-related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials. Heart Fail Rev. 2021;26(6):1437–1445. doi: 10.1007/s10741-020-09942-y

[62]

Dludla P.V., Nyambuya T.M., Johnson R., et al. Metformin and heart failure-related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials // Heart Fail Rev. 2021. Vol. 26, N 6. P. 1437–1445. doi: 10.1007/s10741-020-09942-y

[63]

Ning P, Luo A, Mu X, et al. Exploring the dual character of metformin in Alzheimer’s disease. Neuropharmacology. 2022;207:108966. doi: 10.1016/j.neuropharm.2022.108966

[64]

Ning P., Luo A., Mu X., et al. Exploring the dual character of metformin in Alzheimer’s disease // Neuropharmacology. 2022. Vol. 207. ID 108966. doi: 10.1016/j.neuropharm.2022.108966

[65]

Alshahrani A, Aljada A, Masood A, et al. Proteomic profiling identifies distinct regulation of proteins in obese diabetic patients treated with metformin. Pharmaceuticals (Basel). 2023;16(10):1345. doi: 10.3390/ph16101345

[66]

Alshahrani A., Aljada A., Masood A., et al. Proteomic profiling identifies distinct regulation of proteins in obese diabetic patients treated with metformin // Pharmaceuticals (Basel). 2023. Vol. 16, N 10. ID 1345. doi: 10.3390/ph16101345

[67]

Frank-Podlech S, von Schnurbein J, Veit R, et al. Leptin replacement reestablishes brain insulin action in the hypothalamus in congenital leptin deficiency. Diabetes Care. 2018;41(4):907–910. doi: 10.2337/dc17-1867

[68]

Frank-Podlech S., von Schnurbein J., Veit R., et al. Leptin replacement reestablishes brain insulin action in the hypothalamus in congenital leptin deficiency // Diabetes Care. 2018. Vol. 41, N 4. P. 907–910. doi: 10.2337/dc17-1867

[69]

Hallschmid M. Intranasal insulin. J Neuroendocrinol. 2021;33(4): e12934. doi: 10.1111/jne.12934

[70]

Hallschmid M. Intranasal insulin // J Neuroendocrinol. 2021. Vol. 33, N 4. ID e12934. doi: 10.1111/jne.12934

[71]

Pereira S, Cline DL, Glavas MM, et al. Tissue-specific effects of leptin on glucose and lipid metabolism. Endocr Rev. 2021;42(1):1–28. doi: 10.1210/endrev/bnaa027

[72]

Pereira S., Cline D.L., Glavas M.M., et al. Tissue-specific effects of leptin on glucose and lipid metabolism // Endocr Rev. 2021. Vol. 42, N 1. P. 1–28. doi: 10.1210/endrev/bnaa027

[73]

Air EL, Benoit SC, Clegg DJ, et al. Insulin and leptin combine additively to reduce food intake and body weight in rats. Endocrinology. 2002;143(6):2449–2452. doi: 10.1210/endo.143.6.8948

[74]

Air E.L., Benoit S.C., Clegg D.J., et al. Insulin and leptin combine additively to reduce food intake and body weight in rats // Endocrino¬logy. 2002. Vol. 143, N 6. P. 2449–2452. doi: 10.1210/endo.143.6.8948

[75]

Burcelin R, Thorens B, Glauser M, et al. Gonadotropin-releasing hormone secretion from hypothalamic neurons: stimulation by insulin and potentiation by leptin. Endocrinology. 2003;144(10): 4484–4491. doi: 10.1210/en.2003-0457

[76]

Burcelin R., Thorens B., Glauser M., et al. Gonadotropin-releasing hormone secretion from hypothalamic neurons: stimulation by insulin and potentiation by leptin // Endocrinology. 2003. Vol. 144, N 10. P. 4484–4491. doi: 10.1210/en.2003-0457

[77]

Paz-Filho G, Esposito K, Hurwitz B, et al. Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients. Am J Physiol Endocrinol Metab. 2008;295(6):E1401–E1408. doi:10.1152/ajpendo.90450.2008

[78]

Paz-Filho G., Esposito K., Hurwitz B., et al. Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients // Am J Physiol Endocrinol Metab. 2008. Vol. 295, N 6. P. E1401–E1408. doi: 10.1152/ajpendo.90450.2008

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