Objective To investigate the correlation of interleukin(IL)-1,IL-6 and IL-10 concentrations to ovarian hyperstimulation syndrome(OHSS) and whether intravenous immunoglobulin(IVIG) has the effects on ovarian hyp...Objective To investigate the correlation of interleukin(IL)-1,IL-6 and IL-10 concentrations to ovarian hyperstimulation syndrome(OHSS) and whether intravenous immunoglobulin(IVIG) has the effects on ovarian hyperstimulated rats. Methods Immature female Wistar rats were divided into control group, OHSS group (n=13) and IVIG group(n=13). For the latter two groups, pregnancy mare serum gonadotropin(PMSG)and human chorionic gonadotropin(hCG) were given to induce OHSS, and rats in IVIG group were treated with immunoglobulin. Forty-eight hours after administration of hCG, capillary permeability was evaluated from the Evans blue dye(EB) concentration in the ovaries and the EB concentration in peritoneal irrigated fluid at 30 min after the intravenous injection of EB. Rats' blood samples and ovaries were obtained to be measured for IL-1, IL-6 and IL-10 by ELISA. Results In OHSS group, total weights of bilateral ovaries and the ovarian EB concentration were significantly higher than those in others(P〈0.05). Both serum and ovarian concentrations of IL-1 were significantly higher in OHSS and IVIG groups than those in control group (P〈0.05). The ovarian concentrations of IL-6 and IL-10 in IVIG group were significantly lower than those in control group(P〈0.05). Furthermore, the ovarian IL-10 concentration in IVIG group was significantly lower than that in OHSS group(P〈0. 05). Conclusion Inflammation involved IL-1 in OHSS rats plays an important role. Vascular permeability was mostly increased in ovaries of hyperstimulated rats. It appears that ovaries of OHSS rats may be the primary places of inflammation. IVIG treatment resulted in statistically significant reductions in ovaries' weights and ovarian vascular permeability of OHSS rats, with a decreased level of ovarian IL-10. It implys that IVIG have a beneficial effect in reducing the severity of OHSS in the experimental model maybe by restrainning IL-10.展开更多
Objective: To compare the effectiveness of two methods in preventing ovarian hyperstimulation syndrome (OHSS) with cabergoline and coasting. Design: Systematic review and meta-analysis of randomized clinical trials (R...Objective: To compare the effectiveness of two methods in preventing ovarian hyperstimulation syndrome (OHSS) with cabergoline and coasting. Design: Systematic review and meta-analysis of randomized clinical trials (RCTs). Patients: Women were considered as have risk of OHSS undergoing fertility treatment. Interventions: Cabergoline, coasting. Result: There were included five RCT studies. The clinical pregnancy rate was no significantly difference between two groups (RR 1.22, 95% CI [0.86, 1.71]), implantation rate (RR 1.00, 95% CI [0.75, 1.32]), severe OHSS (RR 0.93, 95% CI [0.38, 2.31]), fertilization rate (SMD 0.70, 95% CI [-0.10, 1.50]), number of oocytes retrieved (SMD 0.80, 95% CI [0.30, 1.30]), number of embryo transfer (SMD-0.04, 95% CI [-0.24, 0.17]), E2 value on the day of HCG injection (SMD 0.21, 95% CI [-0.25, 0.68]), number of MII oocytes (SMD 0.71, 95% CI [0.32, 1.11]), abortion rate (RR 0.61, 95% CI [0.21, 1.83]), number of follicles > 17 mm on day of HCG (SMD -0.01, 95% CI [-0.26, 0.24]), number of follicles 15 - 17 mm on day of HCG (SMD -0.08, 95% CI [-0.33, 0.17]), number of follicles 10 - 14 mm on day of HCG (SMD -0.06, 95% CI [-0.31, 0.19]). Conclusion: Both cabergoline and coasting prevent the occurrence of OHSS, but no statistically significant difference between them. Compared with coasting group, a daily dose of 0.5 mg cabergoline significantly increased the number of oocytes retrieved, MII oocytes, and fertilization rate, but decreased the abortion rate.展开更多
Background: OHSS is a dangerous and potentially life-threatening condition for which many researchers look for new ways to treat. Aim: To determine the effectiveness of prophylactic cabergoline administration on prola...Background: OHSS is a dangerous and potentially life-threatening condition for which many researchers look for new ways to treat. Aim: To determine the effectiveness of prophylactic cabergoline administration on prolactine levels in patients with high risk for ovarian hyperstimulation syndrome (OHSS). Material and Methods: 163 in vitro fertilisation (IVF) patients with high risk for OHSS were enrolled in the study. The criteria for inclusion were more than 15 oocytes retrieved at oocyte pick up. A standard antagonist protocol was used for ovulation induction. Cabergoline treatments (0.5 mg/day) were started on the day of oocyte retrieval and continued for eight days. Prolactine levels were measured at the day of oocyte retrieval and the 9th day after the oocyte retrieval. Results: Of the 163 patients, 26 (15.9%) had OHSS. Prolactine levels on the day of oocyte retrieval were 44.22 ± 24.78 ng/mL and 37.6 ± 22.5 ng/mL in patients with OHSS and without OHSS, respectively (P > 0.05). In contrary prolactine levels were significantly higher in patients with OHSS patients (3.9 ± 5.07 ng/mL) than in patients without OHSS (2.1 ± 2.92 ng/mL) at the 9th day after oocyte retrieval (P < 0.05). Conclusion: Prolactine levels were higher in patients with OHSS than without OHSS who were treated with cabergoline for the prevention of OHSS.展开更多
Objective To explore whether the serum concentrations of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) could serve as the predictors of ovarian hyperstimulation syndrome (...Objective To explore whether the serum concentrations of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) could serve as the predictors of ovarian hyperstimulation syndrome (OHSS) in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). Methods Enzyme-linked immunoadsordent assay (ELISA) was employed to measure the serum concentrations of VEGF and PEDF on the day of hCG administration, oocyte retrieval and embryo transfer, respectively. Based on OHSS classification of the criteria of Golan, 85 patients were divided into three groups. Patients in group A (n=10) showed symptoms of severe OHSS and patients in group B (n=13) suffered from moderate OHSS. The control group (group C, n=62) contained patients without symptoms of OHSS as well as patients with mild OHSS.Results In groups A, B and C, serum concentrations of PEDF on the day of hCG administration (h-PEDF)(166.54 ± 102.81 pg/ml, 159.45 ±136. 77 pg/ml, 172.05±170.95 pg/ml, P=0.48), oocyte retrieval (o-PEDF)(176.91 ± 103.37 pg/ml, 122.52± 92.54 pg/ml, 179.82±177.47 pg/ml, P=0.27) and embryo transfer (e-PEDF)(169.02± 240.08 pg/ml, 136.80 ±139.21pg/ml, 157.38 ±222.54 pg/ml, P=0.95), h-VEGF (175.55 ± 103.54 pg/ml, 218.84 ±179.70pg/ml, 153.39±145.06 pg/ml, P=0.36) and o- VEGF (171.93 ± 128.55 pg/ml, 220.36±149.82 pg/ml, 138. 74 ±% 139.30 pg/ml, P=0. 15) showed no significant differences. There was a statistical difference in serum concentration of e-VEGF between group A (197.04±156.63 pg/ml) and group C (110.69±49.55 pg/ml)(P=0.008). The serum level of estradiol showed a positive correlation with the count of large follicles (r=0. 744). The ratios of h-VEGF/h-PEDF, o-VEGF/o-PEDF and e-VEGF/e-PEDF were calculated and showed a clear difference among groups A, B and C (4.04±3.39, 2.10±2.14, 1.05± 4.80, P〈0.001; 4.54 5.69, 2.29 ±1.67, 0.94 ±0.59, P〈0.001; 5.43±6.16, 1.81±1.36, 2.42±2.60, P=0.04). Conclusion While neither serum concentrations of VEGF nor PEDF can be used as an OHSS predictor, the ratios of h-VEGF/h-PEDF, o-VEGF/o-PEDF and e-VEGF/e-PEDF may have great predictive value.展开更多
Objective To explore the association of genetic polymorphisms in the genes encoding the anti-Miillerian hormone (AMH) and its type H receptor (AMHRII) with ovarian hyperstimulation syndrome (OHSS). Methods Using...Objective To explore the association of genetic polymorphisms in the genes encoding the anti-Miillerian hormone (AMH) and its type H receptor (AMHRII) with ovarian hyperstimulation syndrome (OHSS). Methods Using polymerase chain reaction (PCR) and DNA sequencing techniques, the exons of AMH and AMHRII were analyzed in 27 OHSS patients (OHSS group) and 22 non-OHSS patients (control group) who were applied controlled ovarian hyper- stimulation (COH). Single nucleotide polymorphisms (SNPs) were also analyzed. Results SNPs G〉 T at position 146 of AMH exon 1 and G〉 A at position 134 of AMH exon 2 showed significant differences between the OHSS group and control group (P〈0.05). SNP G〉 T at position 303 of AMH exon 1 showed no significant difference between the OHSS group and control group (P〉0.05). No SNP was detected from the AMHR H exons 1 to 11 in either groups. Conclusion Genetic polymorphisms in the AMH gene may be a cause of ovarian hypersensitivity to exogenous hormone stimulation and the development of OHSS.展开更多
Objective To assess the efficacy of adding Gn-releasing hormone antagonist(GnR HA) on the day of hC G triggering in a long luteal protocol without withholding the agonist in women who are at a risk to develop ovaria...Objective To assess the efficacy of adding Gn-releasing hormone antagonist(GnR HA) on the day of hC G triggering in a long luteal protocol without withholding the agonist in women who are at a risk to develop ovarian hyperstimulation syndrome(OHSS).Methods This was a retrospective cohort study conducted upon 50 women who have elevated serum estradiol(E2) level 〉4 500 ng/L at the day of ovum triggering with hC G on a long agonist luteal protocol of controlled ovarian stimulation(COS). When an exaggerated ovarian response was observed around day 10 of stimulation, immediately the next morning at 6 a.m. gonadotropin administration was stopped or reduced, and a single dose of ganirelix acetate(antagonist) was given sc continuation of the agonist dose hC G. Another serum E2 measurement was done at 6 p.m.(after 12 h of antagonist) then hC G, sc 250 mg and choriogonadotropin α were administered 14 h later after antagonist and documented the reduction of E2 level. Oocyte retrieval was conducted after 34-36 h of hC G administration. The measured outcomes were the level of E2 on the day of hC G injection, number of oocytes and their quality, pregnancy rate and the occurrence of OHSS and its grade in case it happened.Results The total dose for recombinant FSH was 25.3±6.4 ampoules(75 IU/ampoule) while it was 11.0±3.0 ampoules for the urinary hM G. A higher oocyte maturation rate(82.8%) and a high fertilization rate(87.8%) were observed. The mean endometrial thickness was 10.1±1.0 mm on the day of hC G triggering. The higher fertilization rate with the good endometrial thickness observed resulting in a higher pregnancy rate(78.0%, 39/50) with statistically significant(P〈0.05). A significant reduction of E2 level was documented by a percentage around 40% before hC Ginjection. There were no reported cases of severe or moderate OHSS, however 13 cases(26%) were reported to have mild OHSS constituting.Conclusion Acceleration of coasting in cases of OHSS through treatment with GnR HA after pituitary suppression with GnR H agonist(GnR H-a) offered a novel approach to decrease E2 level, avoided cycle cancellation, and maintain excellent oocyte maturation rate, and finally result in high pregnancy rate with prevention of OHSS.展开更多
Objective To report a case of ovarian hemorrhage after transvaginal ultrasoundguided oocyte retrieval combined with severe ovarian hyperstimulation syndrome (OHSS). Methods A 26-year-old woman who was on therapy for...Objective To report a case of ovarian hemorrhage after transvaginal ultrasoundguided oocyte retrieval combined with severe ovarian hyperstimulation syndrome (OHSS). Methods A 26-year-old woman who was on therapy for infertility presented with abdominal distension and a decrease of urine after transvaginal ultrasound-guided oocyte retrieval for in vitro fertilization-embryo transfer (IVF-ET). Initial clinical presentation, ultrasound, and lab results were consistent with the diagnosis of severe OHSS. However with 4 d conservative treatments there seemed no recovery and the patient became more serious for her hemoglobin fell from 169.0 g/L to 60.2 g/L along with more abdominal fluid and a decrease of urine. Ultrasound guided paracentesis revealed an ovarian hemorrhage, and the patient underwent emergent surgery. Results The patient underwent emergent laparotomy for oophoroplasty and preservation of ovary. She got twin pregnancy in the second frozen-thawed embryo transfer (FET) cycle and delivered two female babies. Conclusion It is important to distinguish the OHSS from ovarian hemorrhage, because the ovarian hemorrhage with hemoperitoneum requires immediate operative management, whereas OHSS is nearly always managed conservatively. Clinicians must be aware that ovarian hemorrhage may be delayed in women presenting OHSS.展开更多
基金Nangjing Medicine Science and Technology Development Fund(No:YKK06100)
文摘Objective To investigate the correlation of interleukin(IL)-1,IL-6 and IL-10 concentrations to ovarian hyperstimulation syndrome(OHSS) and whether intravenous immunoglobulin(IVIG) has the effects on ovarian hyperstimulated rats. Methods Immature female Wistar rats were divided into control group, OHSS group (n=13) and IVIG group(n=13). For the latter two groups, pregnancy mare serum gonadotropin(PMSG)and human chorionic gonadotropin(hCG) were given to induce OHSS, and rats in IVIG group were treated with immunoglobulin. Forty-eight hours after administration of hCG, capillary permeability was evaluated from the Evans blue dye(EB) concentration in the ovaries and the EB concentration in peritoneal irrigated fluid at 30 min after the intravenous injection of EB. Rats' blood samples and ovaries were obtained to be measured for IL-1, IL-6 and IL-10 by ELISA. Results In OHSS group, total weights of bilateral ovaries and the ovarian EB concentration were significantly higher than those in others(P〈0.05). Both serum and ovarian concentrations of IL-1 were significantly higher in OHSS and IVIG groups than those in control group (P〈0.05). The ovarian concentrations of IL-6 and IL-10 in IVIG group were significantly lower than those in control group(P〈0.05). Furthermore, the ovarian IL-10 concentration in IVIG group was significantly lower than that in OHSS group(P〈0. 05). Conclusion Inflammation involved IL-1 in OHSS rats plays an important role. Vascular permeability was mostly increased in ovaries of hyperstimulated rats. It appears that ovaries of OHSS rats may be the primary places of inflammation. IVIG treatment resulted in statistically significant reductions in ovaries' weights and ovarian vascular permeability of OHSS rats, with a decreased level of ovarian IL-10. It implys that IVIG have a beneficial effect in reducing the severity of OHSS in the experimental model maybe by restrainning IL-10.
文摘Objective: To compare the effectiveness of two methods in preventing ovarian hyperstimulation syndrome (OHSS) with cabergoline and coasting. Design: Systematic review and meta-analysis of randomized clinical trials (RCTs). Patients: Women were considered as have risk of OHSS undergoing fertility treatment. Interventions: Cabergoline, coasting. Result: There were included five RCT studies. The clinical pregnancy rate was no significantly difference between two groups (RR 1.22, 95% CI [0.86, 1.71]), implantation rate (RR 1.00, 95% CI [0.75, 1.32]), severe OHSS (RR 0.93, 95% CI [0.38, 2.31]), fertilization rate (SMD 0.70, 95% CI [-0.10, 1.50]), number of oocytes retrieved (SMD 0.80, 95% CI [0.30, 1.30]), number of embryo transfer (SMD-0.04, 95% CI [-0.24, 0.17]), E2 value on the day of HCG injection (SMD 0.21, 95% CI [-0.25, 0.68]), number of MII oocytes (SMD 0.71, 95% CI [0.32, 1.11]), abortion rate (RR 0.61, 95% CI [0.21, 1.83]), number of follicles > 17 mm on day of HCG (SMD -0.01, 95% CI [-0.26, 0.24]), number of follicles 15 - 17 mm on day of HCG (SMD -0.08, 95% CI [-0.33, 0.17]), number of follicles 10 - 14 mm on day of HCG (SMD -0.06, 95% CI [-0.31, 0.19]). Conclusion: Both cabergoline and coasting prevent the occurrence of OHSS, but no statistically significant difference between them. Compared with coasting group, a daily dose of 0.5 mg cabergoline significantly increased the number of oocytes retrieved, MII oocytes, and fertilization rate, but decreased the abortion rate.
文摘Background: OHSS is a dangerous and potentially life-threatening condition for which many researchers look for new ways to treat. Aim: To determine the effectiveness of prophylactic cabergoline administration on prolactine levels in patients with high risk for ovarian hyperstimulation syndrome (OHSS). Material and Methods: 163 in vitro fertilisation (IVF) patients with high risk for OHSS were enrolled in the study. The criteria for inclusion were more than 15 oocytes retrieved at oocyte pick up. A standard antagonist protocol was used for ovulation induction. Cabergoline treatments (0.5 mg/day) were started on the day of oocyte retrieval and continued for eight days. Prolactine levels were measured at the day of oocyte retrieval and the 9th day after the oocyte retrieval. Results: Of the 163 patients, 26 (15.9%) had OHSS. Prolactine levels on the day of oocyte retrieval were 44.22 ± 24.78 ng/mL and 37.6 ± 22.5 ng/mL in patients with OHSS and without OHSS, respectively (P > 0.05). In contrary prolactine levels were significantly higher in patients with OHSS patients (3.9 ± 5.07 ng/mL) than in patients without OHSS (2.1 ± 2.92 ng/mL) at the 9th day after oocyte retrieval (P < 0.05). Conclusion: Prolactine levels were higher in patients with OHSS than without OHSS who were treated with cabergoline for the prevention of OHSS.
文摘Objective To explore whether the serum concentrations of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) could serve as the predictors of ovarian hyperstimulation syndrome (OHSS) in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). Methods Enzyme-linked immunoadsordent assay (ELISA) was employed to measure the serum concentrations of VEGF and PEDF on the day of hCG administration, oocyte retrieval and embryo transfer, respectively. Based on OHSS classification of the criteria of Golan, 85 patients were divided into three groups. Patients in group A (n=10) showed symptoms of severe OHSS and patients in group B (n=13) suffered from moderate OHSS. The control group (group C, n=62) contained patients without symptoms of OHSS as well as patients with mild OHSS.Results In groups A, B and C, serum concentrations of PEDF on the day of hCG administration (h-PEDF)(166.54 ± 102.81 pg/ml, 159.45 ±136. 77 pg/ml, 172.05±170.95 pg/ml, P=0.48), oocyte retrieval (o-PEDF)(176.91 ± 103.37 pg/ml, 122.52± 92.54 pg/ml, 179.82±177.47 pg/ml, P=0.27) and embryo transfer (e-PEDF)(169.02± 240.08 pg/ml, 136.80 ±139.21pg/ml, 157.38 ±222.54 pg/ml, P=0.95), h-VEGF (175.55 ± 103.54 pg/ml, 218.84 ±179.70pg/ml, 153.39±145.06 pg/ml, P=0.36) and o- VEGF (171.93 ± 128.55 pg/ml, 220.36±149.82 pg/ml, 138. 74 ±% 139.30 pg/ml, P=0. 15) showed no significant differences. There was a statistical difference in serum concentration of e-VEGF between group A (197.04±156.63 pg/ml) and group C (110.69±49.55 pg/ml)(P=0.008). The serum level of estradiol showed a positive correlation with the count of large follicles (r=0. 744). The ratios of h-VEGF/h-PEDF, o-VEGF/o-PEDF and e-VEGF/e-PEDF were calculated and showed a clear difference among groups A, B and C (4.04±3.39, 2.10±2.14, 1.05± 4.80, P〈0.001; 4.54 5.69, 2.29 ±1.67, 0.94 ±0.59, P〈0.001; 5.43±6.16, 1.81±1.36, 2.42±2.60, P=0.04). Conclusion While neither serum concentrations of VEGF nor PEDF can be used as an OHSS predictor, the ratios of h-VEGF/h-PEDF, o-VEGF/o-PEDF and e-VEGF/e-PEDF may have great predictive value.
基金supported by a scientific research grant from Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technologythe National Natural Science Fund (Project No. 81200474)
文摘Objective To explore the association of genetic polymorphisms in the genes encoding the anti-Miillerian hormone (AMH) and its type H receptor (AMHRII) with ovarian hyperstimulation syndrome (OHSS). Methods Using polymerase chain reaction (PCR) and DNA sequencing techniques, the exons of AMH and AMHRII were analyzed in 27 OHSS patients (OHSS group) and 22 non-OHSS patients (control group) who were applied controlled ovarian hyper- stimulation (COH). Single nucleotide polymorphisms (SNPs) were also analyzed. Results SNPs G〉 T at position 146 of AMH exon 1 and G〉 A at position 134 of AMH exon 2 showed significant differences between the OHSS group and control group (P〈0.05). SNP G〉 T at position 303 of AMH exon 1 showed no significant difference between the OHSS group and control group (P〉0.05). No SNP was detected from the AMHR H exons 1 to 11 in either groups. Conclusion Genetic polymorphisms in the AMH gene may be a cause of ovarian hypersensitivity to exogenous hormone stimulation and the development of OHSS.
文摘Objective To assess the efficacy of adding Gn-releasing hormone antagonist(GnR HA) on the day of hC G triggering in a long luteal protocol without withholding the agonist in women who are at a risk to develop ovarian hyperstimulation syndrome(OHSS).Methods This was a retrospective cohort study conducted upon 50 women who have elevated serum estradiol(E2) level 〉4 500 ng/L at the day of ovum triggering with hC G on a long agonist luteal protocol of controlled ovarian stimulation(COS). When an exaggerated ovarian response was observed around day 10 of stimulation, immediately the next morning at 6 a.m. gonadotropin administration was stopped or reduced, and a single dose of ganirelix acetate(antagonist) was given sc continuation of the agonist dose hC G. Another serum E2 measurement was done at 6 p.m.(after 12 h of antagonist) then hC G, sc 250 mg and choriogonadotropin α were administered 14 h later after antagonist and documented the reduction of E2 level. Oocyte retrieval was conducted after 34-36 h of hC G administration. The measured outcomes were the level of E2 on the day of hC G injection, number of oocytes and their quality, pregnancy rate and the occurrence of OHSS and its grade in case it happened.Results The total dose for recombinant FSH was 25.3±6.4 ampoules(75 IU/ampoule) while it was 11.0±3.0 ampoules for the urinary hM G. A higher oocyte maturation rate(82.8%) and a high fertilization rate(87.8%) were observed. The mean endometrial thickness was 10.1±1.0 mm on the day of hC G triggering. The higher fertilization rate with the good endometrial thickness observed resulting in a higher pregnancy rate(78.0%, 39/50) with statistically significant(P〈0.05). A significant reduction of E2 level was documented by a percentage around 40% before hC Ginjection. There were no reported cases of severe or moderate OHSS, however 13 cases(26%) were reported to have mild OHSS constituting.Conclusion Acceleration of coasting in cases of OHSS through treatment with GnR HA after pituitary suppression with GnR H agonist(GnR H-a) offered a novel approach to decrease E2 level, avoided cycle cancellation, and maintain excellent oocyte maturation rate, and finally result in high pregnancy rate with prevention of OHSS.
文摘Objective To report a case of ovarian hemorrhage after transvaginal ultrasoundguided oocyte retrieval combined with severe ovarian hyperstimulation syndrome (OHSS). Methods A 26-year-old woman who was on therapy for infertility presented with abdominal distension and a decrease of urine after transvaginal ultrasound-guided oocyte retrieval for in vitro fertilization-embryo transfer (IVF-ET). Initial clinical presentation, ultrasound, and lab results were consistent with the diagnosis of severe OHSS. However with 4 d conservative treatments there seemed no recovery and the patient became more serious for her hemoglobin fell from 169.0 g/L to 60.2 g/L along with more abdominal fluid and a decrease of urine. Ultrasound guided paracentesis revealed an ovarian hemorrhage, and the patient underwent emergent surgery. Results The patient underwent emergent laparotomy for oophoroplasty and preservation of ovary. She got twin pregnancy in the second frozen-thawed embryo transfer (FET) cycle and delivered two female babies. Conclusion It is important to distinguish the OHSS from ovarian hemorrhage, because the ovarian hemorrhage with hemoperitoneum requires immediate operative management, whereas OHSS is nearly always managed conservatively. Clinicians must be aware that ovarian hemorrhage may be delayed in women presenting OHSS.