黄体酮对大鼠神经痛的镇痛作用及机制研究
发布时间：2018-09-08 18:05
【摘要】：目的黄体酮(又称孕酮)是一种类固醇激素,可以在雌性动物的卵巢和胎盘合成,常用于妇产科学。近几年研究表明,神经系统也可以生成黄体酮,如神经胶质细胞,主要是少突胶质和星形胶质。且有研究表明,在神经系统中,黄体酮通过调节基因的转录、细胞内的信号通路和神经传导而发挥了多效性。近年来有少量文献报道,黄体酮可以减轻CCI(Chronic constrictive injury)诱导的疼痛行为,并且可以修复外周的运动及感觉神经纤维上电生理的变化,提示黄体酮对于神经痛具有治疗作用,但其具体机制并不清楚。本实验拟用L5脊神经结扎(Spinal Nerve Ligation,SNL)造成的神经病理性疼痛模型大鼠,应用行为学和免疫荧光染色法分别检测孕酮对疼痛行为的影响及对小胶质细胞和星形胶质细胞活化的影响,并用ELISA蛋白测定方法对腰骶膨大处脊髓和L5神经节中COX-2(Cyclooxygenase-2)和i NOS(inducible nitric oxide synthase)蛋白表达的影响,以探讨黄体酮的镇痛机制。方法实验一:建造脊神经结扎模型。术后第3天开始测量大鼠术侧和对侧的机械缩足阈值,直到术后第21天,以检测大鼠疼痛阈值的经时变化过程。取无痛觉过敏和痛觉迟钝的正常雄性Sprague-Dawley大鼠24只,将其随机的分为三组:正常组、假手术组和手术组。用von Frey细丝测定实验大鼠机械缩足阈值,以50%的缩足阈值(50%paw withdrawal threshold,50%PWT)表示,绘制模型大鼠的时间-疼痛行为变化曲线。实验二:黄体酮对大鼠机械缩足阈值的影响。取健康成年雄性SD大鼠32只,随机分为4组:正常组、空白对照组和黄体酮低剂量(8 mg/kg)及高剂量组(16mg/kg)。正常组大鼠不做任何处理;空白对照组大鼠于SNL手术当天开始,皮下注射助溶剂即22.5%环糊精溶液(注射容积:3ml/kg体重),正常组亦皮下注射22.5%环糊精溶液,每天一次,连续21天;实验组大鼠分别皮下注射低剂量(8 mg/kg/d)和高剂量(16mg/kg/d)的黄体酮。各组大鼠分别于SNL术前6天开始测量,运用von Frey细丝检测大鼠后足的机械缩足阈值,每天测定一次,直到术后的第21天。升降法测定大鼠50%机械性收缩阈值。实验三:黄体酮对大鼠胶质细胞激活的影响。分别于给药后3天、7天、14天及21天,行为学测定后灌流,取脊髓腰骶膨大处,做冰冻切片,对星胶质细胞的标志物GFAP(glial fibrillary acidic protein)以及小胶质细胞的标志物OX-42进行免疫染色,在共聚焦显微镜下观察其表达变化。实验四:黄体酮对大鼠腰骶膨大处脊髓和L5神经节内COX-2和i NOS蛋白表达的影响。取健康成年雄性SD大鼠24只,随机分为3组:正常组、空白对照组及黄体酮组(16 mg/kg)。正常组大鼠不做任何处理;空白对照组大鼠于SNL术后开始,皮下注射助溶剂即22.5%环糊精溶液(注射容积:3ml/kg体重),每天一次,连续21天;实验组大鼠皮下注射高剂量(16mg/kg)的黄体酮,每天一次,连续21天;分别于3天、7天、14天及21天给药1h后灌流,取脊髓腰骶膨大处和术侧L5神经节,用ELISA试剂盒测定腰骶膨大处脊髓和L5神经节中COX-2和i NOS蛋白表达量。结果1.SNL脊神经结扎后机械性疼痛阈值经时变化曲线SNL术后第3天开始缩足阈值显著降低,此后缩足阈值基本维持在5g以下。SNL术后第14天开始,机械缩足阈值开始逐渐上升,直到第21天,但和假手术组相比,术侧机械缩足阈值依然很低(P0.05),从SNL术后的第3天开始直到第13天,试验大鼠的缩足阈值维持在一个较稳定的水平(P0.01)。2.SNL脊神经结扎后连续皮下注射黄体酮对机械缩足阈值的影响皮下注射黄体酮显著提高了术侧后足的机械缩足阈值。正常组、空白对照组、黄体酮低剂量组(8 mg/kg)和高剂量组(16 mg/kg)的术侧(左侧)机械缩足阈值术前分别是14.29±1.63g、14.41±1.01g、14.27±1.02g和14.49±0.95g;给药3天后分别为14.74±0.73、3.84±1.09g、4.47±0.96g和4.59±1.47g;给药7天后分别为14.49±0.95、3.47±1.78g、4.76±1.72g和5.41±0.76g;给药14天后分别为14.32±1.30、4.39±0.61g、5.48±0.54g和7.20±0.81g;给药21天后分别为14.33±0.93g、5.37±0.98g、8.55±1.10g、11.65±1.83g。结果表明,术后第14天和第21天,黄体酮高剂量组(16 mg/kg)、低剂量组(8 mg/kg)和空白对照组相比,机械缩足阈值显著增加(分别是P0.05,P0.01),且黄体酮高剂量组(16 mg/kg)和黄体酮低剂量组(8 mg/kg)对比,机械缩足阈值显著增加(P0.01)。黄体酮对手术对侧的痛阈无显著影响。3.SNL脊神经结扎后连续皮下注射黄体酮对OX-42表达的影响免疫染色的结果表明,脊神经结扎后会使脊髓中的小胶质细胞活化。小胶质细胞激活后,由静息状态的分枝状分化成活化状态的阿米巴状。SNL术后小胶质细胞的标志物OX-42免疫染色强度经过统计分析后表明:正常组中OX-42的活化量很低,处于基线水平。与空白对照组相比,黄体酮组第3天的术侧光密度值及第7天的术侧光密度值(IOD)无统计学意义(P㧐0.05)。与空白对照组相比,黄体酮组第14天术侧光密度值(IOD)和第21天的术侧光密度值(IOD)具有统计学意义(均为P0.01)。黄体酮抑制了SNL后小胶质细胞激活。4.SNL脊神经结扎后连续皮下注射黄体酮对GFAP表达的影响免疫染色的结果表明,脊神经结扎后使脊髓中的星胶质细胞活化。星胶质活化后,形态及数量会发生一定的改变,表现为增生、肥大,星胶质细胞的标志物GFAP免疫染色的强度在经过统计分析后表明,正常组中GFAP的表达量很低,位于基线水平。与空白对照组相比,黄体酮组第3天的术侧光密度值和第7天的术侧光密度值(IOD)无统计学意义(P㧐0.05)。与空白对照组相比,黄体酮组第14天术侧光密度值(IOD)和第21天的术侧光密度值(IOD)具有统计学意义(均为P0.01)。黄体酮抑制了SNL后星胶质细胞激活。5.SNL脊神经结扎后连续皮下注射黄体酮对COX-2以及i NOS两种酶表达的影响。连续的皮下注射黄体酮显著的降低了脊髓背角和神经节中COX-2和i NOS两种蛋白的表达量。COX-2和i NOS蛋白在正常组大鼠的腰骶膨大处脊髓背角和L5神经节中的表达量很低,其平均含量分别为11.24±1.71ng/L、7.71±1.29 ng/L和0.80±0.09μmol/L、0.58±0.11μmol/L。SNL术后两种蛋白的浓度急剧升高,COX-2和i NOS蛋白在空白对照组中大鼠的腰骶膨大处脊髓背角和L5神经节中的平均表达量分别为84.10±8.62 ng/L、88.85±6.91 ng/L和7.40±0.59μmol/L、7.58±0.60μmol/L。连续皮下注射黄体酮第3天和第7天,与空白对照组相比,COX-2和i NOS两种蛋白的表达量没有统计学意义(P㧐0.05)。黄体酮治疗组中,COX-2第3天在腰骶膨大处脊髓背角和L5神经节中的表达量分别为84.59±9.23ng/L、87.56±8.26 ng/L,i NOS第3天在腰骶膨大处脊髓背角和L5神经节中的表达量分别为7.45±0.87μmol/L、7.52±1.25μmol/L;COX-2第7天在腰骶膨大处脊髓背角和L5神经节中的表达量分别为80.36±5.96 ng/L、85.29±8.41 ng/L,i NOS第7天在腰骶膨大处脊髓背角和L5神经节中的表达量分别为7.14±0.47μmol/L、7.20±0.91μmol/L;与空白对照组对比,连续用药14天和21天后,两种蛋白表达量具有统计学意义(均为P0.01)。黄体酮治疗组中,COX-2第14天在腰骶膨大处脊髓背角和L5神经节中的表达量分别为58.84±5.44 ng/L、61.21±5.43 ng/L,i NOS第14天在腰骶膨大处脊髓背角和L5神经节中的表达量分别为5.17±0.82μmol/L、5.23±0.58μmol/L;COX-2第21天在腰骶膨大处脊髓背角和L5神经节中的表达量分别为32.77±5.07 ng/L、31.78±8.37 ng/L,i NOS第21天在腰骶膨大处脊髓背角和L5神经节中的表达量分别为2.42±0.29μmol/L、2.40±0.36μmol/L。结论黄体酮可剂量依赖性地抑制大鼠机械性疼痛行为,机制可能与抑制胶质细胞的激活以及降低了腰骶膨大处脊髓背角和L5神经节中COX-2和i NOS两种蛋白的表达有关。
[Abstract]:OBJECTIVE Progesterone (progesterone) is a steroid hormone that can be synthesized in the ovaries and placentas of female animals and is often used in obstetrics and gynecology. Recent studies have shown that the nervous system can also produce progesterone, such as glial cells, mainly oligodendrocytes and astrocytes. Gene transcription, intracellular signaling pathways, and nerve conduction play a multipotent role. In recent years, a small number of literatures have reported that progesterone can alleviate pain behavior induced by CCI, and can repair electrophysiological changes in peripheral motor and sensory nerve fibers, suggesting that progesterone has therapeutic effects on neuralgia. The effect of progesterone on pain behavior and the activation of microglia and astrocytes in rats with neuropathic pain induced by L5 spinal nerve ligation (SNL) was studied by behavioral and immunofluorescence staining. Methods To investigate the effects of progesterone on the expression of COX-2 and inducible nitric oxide synthase in the lumbosacral enlarged spinal cord and L5 ganglion, and to explore the analgesic mechanism of progesterone. On the 21st day, 24 normal male Sprague-Dawley rats were randomly divided into three groups: normal group, sham operation group and operation group. Experiment 2: Effect of progesterone on the threshold of mechanical foot contraction in rats. 32 healthy adult male SD rats were randomly divided into 4 groups: normal group, blank control group, low dose progesterone group (8 mg/kg) and high dose progesterone group (16 mg/kg). Rats in the control group were subcutaneously injected with 22.5% cyclodextrin solution (volume: 3ml / kg body weight) for 21 days. Rats in the control group were subcutaneously injected with 22.5% cyclodextrin solution once a day for 21 consecutive days. Rats in the experimental group were subcutaneously injected with low dose (8mg / kg / d) and high dose (16mg / kg / d) progesterone. At the beginning of the day, von Frey filament was used to detect the mechanical shrinkage threshold of the hind foot of rats, once a day until the 21st day after operation. The mechanical shrinkage threshold of 50% was measured by ascending and descending method. Experiment 3: The effect of progesterone on the activation of glial cells in rats. Immunostaining of GFAP (glial fibrillary acidic protein) and OX-42 (microglia marker) was performed in the lumbosacral enlargement area. The expression of COX-2 and I NOS protein in the spinal cord and L5 ganglion of rats with lumbosacral enlargement was observed under confocal microscope. Twenty-four healthy adult male SD rats were randomly divided into three groups: normal group, blank control group and progesterone group (16 mg/kg). Rats in normal group did not receive any treatment; rats in blank control group were subcutaneously injected with 22.5% cyclodextrin solution (injection volume: 3 ml/kg body weight) once a day for 21 days after SNL operation; rats in experimental group were subcutaneously injected with progesterone for 21 days. High dose progesterone (16mg/kg) was injected once a day for 21 consecutive days, and then perfused at 3, 7, 14 and 21 days for 1 hour. The expression of COX-2 and I NOS in the lumbosacral enlargement and the L5 ganglion was measured by ELISA kit. After SNL operation, the threshold of mechanical foot contraction began to rise gradually from the 14th day to the 21st day, but compared with sham operation group, the threshold of mechanical foot contraction was still very low (P 0.05). From the 3rd day to the 13th day after SNL operation, the threshold of mechanical foot contraction began to rise gradually. Effects of continuous subcutaneous injection of progesterone after spinal nerve ligation on the threshold of mechanical foot contraction in rats (left side) mechanical constriction threshold of the left side (left side) was 14.29 [(1.63 g, 14.41 [(1.63 g, 14.41 [1.01 g, 14.41 [1.01 g, 14.27 [1.02g, 14.27 [1.02g and 14.49 [0.02g] and 14.49 [0.49 [0.73, 3.84 [1.09g, 4.84 [1.09g, 4.47 [0.96 g and 4.47 [0.47 [0.96g and 4.59 [4.59 [1.47] 1.47 [1.47g, 3.47 [1.78 g, 4.76 [1.72g and 5.76 [5.48 [0]. The results showed that on the 14th and 21st days after operation, the mechanical foot shrinkage thresholds of high dose progesterone group (16 mg/kg), low dose progesterone group (8 mg/kg) and blank control group were significantly increased (P 0.05, P 0.01, respectively). Compared with the low dose progesterone group (8 mg/kg), the mechanical foot shrinkage threshold increased significantly (P 0.01). Progesterone had no significant effect on the contralateral pain threshold. 3. The effect of continuous subcutaneous injection of progesterone after spinal nerve ligation on the expression of OX-42. The immunostaining results showed that spinal cord microglia were activated after spinal nerve ligation. OX-42 immunostaining intensity, a marker of microglia after SNL, was statistically analyzed. The activation of OX-42 in the normal group was very low at baseline level. Compared with the control group, the operative side optical density on day 3 and the operation on day 7 in the progesterone group were significantly lower. There was no significant difference in the lateral optical density (IOD) between the progesterone group and the control group (P? 0.05). Compared with the control group, the IOD of the progesterone group on the 14th day and the IOD of the 21th day were statistically significant (all P 0.01). Progesterone inhibited the activation of microglia after SNL. 4. Progesterone injected subcutaneously after spinal nerve ligation inhibited the expression of GFAP. The results of immunostaining showed that the astrocytes in spinal cord were activated after ligation of spinal nerve. After activation of astrocytes, the morphology and number of astrocytes changed to a certain extent, showing hyperplasia and hypertrophy. The intensity of GFAP immunostaining, a marker of astrocytes, showed that the expression of GFAP in the normal group was very low and located in the base. There was no significant difference between the progesterone group and the control group on the 3rd day and the 7th day (P? 0.05). Compared with the control group, the progesterone group had significant difference on the 14th day and the 21st day (both P 0.01). Progesterone inhibited SNL. Posterior astrocyte activation. 5. Effect of progesterone on the expression of COX-2 and I NOS after spinal nerve ligation. Progesterone significantly decreased the expression of COX-2 and I NOS proteins in spinal dorsal horn and ganglion after continuous subcutaneous injection. COX-2 and I NOS proteins in lumbosacral enlargement of normal rats. The expression levels of COX-2 and I NOS in spinal dorsal horn and L5 ganglion of rats in blank control group were 84.10% and 84.10% respectively. The expression of COX-2 and I NOS in spinal dorsal horn and L5 ganglion of lumbosacral enlargement in progesterone treatment group was not significantly different from that in control group (P The expression levels of I NOS in the spinal dorsal horn and L5 ganglion of lumbosacral enlargement on the 3rd day were 7.45 (+ 0.87) and 7.52 (+ 1.25) respectively. The expression levels of COX-2 in the spinal dorsal horn and L5 ganglion of lumbosacral enlargement on the 7th day were 80.36 (+ 5.96 ng/L), 85.29 (+ 8.41 ng/L) and 80.29 (+ 8.41 ng/L) respectively. The expression levels of COX-2 in spinal dorsal horn and L5 ganglion were 7.14 (+ 0.47) and 7.20 (+ 0.91) respectively. Compared with the control group, the expression levels of COX-2 in spinal dorsal horn and L5 ganglion on day 14 and 21 were statistically significant (both P 0.01). The expression levels of COX-2 in spinal dorsal horn and L5 ganglion of lumbosacral enlargement on the 14th day were 5.17 (+ 0.82) and 5.23 (+ 0.58) respectively. The expression levels of COX-2 in spinal dorsal horn and L5 ganglion of lumbosacral enlargement on the 21st day were 32.77 (+ 5.07) ng/L, 31.78 (+ 8.37) ng/L, and I NOS in lumbosacral enlargement on the 21st day. The expression levels of COX-2 and I NOS in spinal dorsal horn and L5 ganglion were 2.42.29 and 2.40.36 0.366550 Close.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R965
[Abstract]:OBJECTIVE Progesterone (progesterone) is a steroid hormone that can be synthesized in the ovaries and placentas of female animals and is often used in obstetrics and gynecology. Recent studies have shown that the nervous system can also produce progesterone, such as glial cells, mainly oligodendrocytes and astrocytes. Gene transcription, intracellular signaling pathways, and nerve conduction play a multipotent role. In recent years, a small number of literatures have reported that progesterone can alleviate pain behavior induced by CCI, and can repair electrophysiological changes in peripheral motor and sensory nerve fibers, suggesting that progesterone has therapeutic effects on neuralgia. The effect of progesterone on pain behavior and the activation of microglia and astrocytes in rats with neuropathic pain induced by L5 spinal nerve ligation (SNL) was studied by behavioral and immunofluorescence staining. Methods To investigate the effects of progesterone on the expression of COX-2 and inducible nitric oxide synthase in the lumbosacral enlarged spinal cord and L5 ganglion, and to explore the analgesic mechanism of progesterone. On the 21st day, 24 normal male Sprague-Dawley rats were randomly divided into three groups: normal group, sham operation group and operation group. Experiment 2: Effect of progesterone on the threshold of mechanical foot contraction in rats. 32 healthy adult male SD rats were randomly divided into 4 groups: normal group, blank control group, low dose progesterone group (8 mg/kg) and high dose progesterone group (16 mg/kg). Rats in the control group were subcutaneously injected with 22.5% cyclodextrin solution (volume: 3ml / kg body weight) for 21 days. Rats in the control group were subcutaneously injected with 22.5% cyclodextrin solution once a day for 21 consecutive days. Rats in the experimental group were subcutaneously injected with low dose (8mg / kg / d) and high dose (16mg / kg / d) progesterone. At the beginning of the day, von Frey filament was used to detect the mechanical shrinkage threshold of the hind foot of rats, once a day until the 21st day after operation. The mechanical shrinkage threshold of 50% was measured by ascending and descending method. Experiment 3: The effect of progesterone on the activation of glial cells in rats. Immunostaining of GFAP (glial fibrillary acidic protein) and OX-42 (microglia marker) was performed in the lumbosacral enlargement area. The expression of COX-2 and I NOS protein in the spinal cord and L5 ganglion of rats with lumbosacral enlargement was observed under confocal microscope. Twenty-four healthy adult male SD rats were randomly divided into three groups: normal group, blank control group and progesterone group (16 mg/kg). Rats in normal group did not receive any treatment; rats in blank control group were subcutaneously injected with 22.5% cyclodextrin solution (injection volume: 3 ml/kg body weight) once a day for 21 days after SNL operation; rats in experimental group were subcutaneously injected with progesterone for 21 days. High dose progesterone (16mg/kg) was injected once a day for 21 consecutive days, and then perfused at 3, 7, 14 and 21 days for 1 hour. The expression of COX-2 and I NOS in the lumbosacral enlargement and the L5 ganglion was measured by ELISA kit. After SNL operation, the threshold of mechanical foot contraction began to rise gradually from the 14th day to the 21st day, but compared with sham operation group, the threshold of mechanical foot contraction was still very low (P 0.05). From the 3rd day to the 13th day after SNL operation, the threshold of mechanical foot contraction began to rise gradually. Effects of continuous subcutaneous injection of progesterone after spinal nerve ligation on the threshold of mechanical foot contraction in rats (left side) mechanical constriction threshold of the left side (left side) was 14.29 [(1.63 g, 14.41 [(1.63 g, 14.41 [1.01 g, 14.41 [1.01 g, 14.27 [1.02g, 14.27 [1.02g and 14.49 [0.02g] and 14.49 [0.49 [0.73, 3.84 [1.09g, 4.84 [1.09g, 4.47 [0.96 g and 4.47 [0.47 [0.96g and 4.59 [4.59 [1.47] 1.47 [1.47g, 3.47 [1.78 g, 4.76 [1.72g and 5.76 [5.48 [0]. The results showed that on the 14th and 21st days after operation, the mechanical foot shrinkage thresholds of high dose progesterone group (16 mg/kg), low dose progesterone group (8 mg/kg) and blank control group were significantly increased (P 0.05, P 0.01, respectively). Compared with the low dose progesterone group (8 mg/kg), the mechanical foot shrinkage threshold increased significantly (P 0.01). Progesterone had no significant effect on the contralateral pain threshold. 3. The effect of continuous subcutaneous injection of progesterone after spinal nerve ligation on the expression of OX-42. The immunostaining results showed that spinal cord microglia were activated after spinal nerve ligation. OX-42 immunostaining intensity, a marker of microglia after SNL, was statistically analyzed. The activation of OX-42 in the normal group was very low at baseline level. Compared with the control group, the operative side optical density on day 3 and the operation on day 7 in the progesterone group were significantly lower. There was no significant difference in the lateral optical density (IOD) between the progesterone group and the control group (P? 0.05). Compared with the control group, the IOD of the progesterone group on the 14th day and the IOD of the 21th day were statistically significant (all P 0.01). Progesterone inhibited the activation of microglia after SNL. 4. Progesterone injected subcutaneously after spinal nerve ligation inhibited the expression of GFAP. The results of immunostaining showed that the astrocytes in spinal cord were activated after ligation of spinal nerve. After activation of astrocytes, the morphology and number of astrocytes changed to a certain extent, showing hyperplasia and hypertrophy. The intensity of GFAP immunostaining, a marker of astrocytes, showed that the expression of GFAP in the normal group was very low and located in the base. There was no significant difference between the progesterone group and the control group on the 3rd day and the 7th day (P? 0.05). Compared with the control group, the progesterone group had significant difference on the 14th day and the 21st day (both P 0.01). Progesterone inhibited SNL. Posterior astrocyte activation. 5. Effect of progesterone on the expression of COX-2 and I NOS after spinal nerve ligation. Progesterone significantly decreased the expression of COX-2 and I NOS proteins in spinal dorsal horn and ganglion after continuous subcutaneous injection. COX-2 and I NOS proteins in lumbosacral enlargement of normal rats. The expression levels of COX-2 and I NOS in spinal dorsal horn and L5 ganglion of rats in blank control group were 84.10% and 84.10% respectively. The expression of COX-2 and I NOS in spinal dorsal horn and L5 ganglion of lumbosacral enlargement in progesterone treatment group was not significantly different from that in control group (P The expression levels of I NOS in the spinal dorsal horn and L5 ganglion of lumbosacral enlargement on the 3rd day were 7.45 (+ 0.87) and 7.52 (+ 1.25) respectively. The expression levels of COX-2 in the spinal dorsal horn and L5 ganglion of lumbosacral enlargement on the 7th day were 80.36 (+ 5.96 ng/L), 85.29 (+ 8.41 ng/L) and 80.29 (+ 8.41 ng/L) respectively. The expression levels of COX-2 in spinal dorsal horn and L5 ganglion were 7.14 (+ 0.47) and 7.20 (+ 0.91) respectively. Compared with the control group, the expression levels of COX-2 in spinal dorsal horn and L5 ganglion on day 14 and 21 were statistically significant (both P 0.01). The expression levels of COX-2 in spinal dorsal horn and L5 ganglion of lumbosacral enlargement on the 14th day were 5.17 (+ 0.82) and 5.23 (+ 0.58) respectively. The expression levels of COX-2 in spinal dorsal horn and L5 ganglion of lumbosacral enlargement on the 21st day were 32.77 (+ 5.07) ng/L, 31.78 (+ 8.37) ng/L, and I NOS in lumbosacral enlargement on the 21st day. The expression levels of COX-2 and I NOS in spinal dorsal horn and L5 ganglion were 2.42.29 and 2.40.36 0.366550 Close.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R965
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