ObjectiveTaking classical herbal pair compatibility research as the entry point， this study aimed to deeply investigate the material basis and compatibility rules underlying the antidepressant effects of the traditional Chinese medicine （TCM） formula Zhizi Houpotang， and to elucidate its antidepressant mechanism， with a particular focus on its regulation of neuroinflammatory responses mediated by the NOD-like receptor protein 3 （NLRP3）/gasdermin D （GSDMD） signaling pathway and the consequent improvement of neuronal synaptic plasticity. MethodsC57BL/6J mice were randomly divided into a blank control group， a chronic unpredictable mild stress （CUMS） depression model group， a Zhizi Houpotang full-formula group （6 g·kg^-1·d^-1）， a Magnoliae Officinalis Cortex （MOC）-Aurantii Fructus Immaturus （AFI） herbal pair group （4.2 g·kg^-1·d^-1）， a Gardeniae Fructus （GF）-MOC herbal pair group （4.2 g·kg^-1·d^-1）， a GF-AFI herbal pair group （3.6 g·kg^-1·d^-1）， and a positive drug group （fluoxetine， 12 mg·kg^-1·d^-1）. Depressive-like behaviors in mice were evaluated using behavioral tests. Immunofluorescence staining was used to label and quantify the expression of the microglial marker ionized calcium-binding adaptor molecule 1 （Ibal） and the purinergic receptor P2X ligand-gated ion channel 7 （P2RX7） in the prefrontal cortex （PFC）. Enzyme-linked immunosorbent assay （ELISA） was applied to detect the levels of inflammatory cytokines interleukin-1β （IL-1β） and interleukin-18 （IL-18） in serum and PFC tissues. Western blot was employed to determine the expression of pannexin 1 （Panx1）， P2RX7， NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， Caspase-1， GSDMD， postsynaptic density protein 95 （PSD95）， and the presynaptic protein Synapsin 1 in PFC tissues. Golgi staining was used to assess dendritic spine density of neurons in the PFC. ResultsCompared with the blank control group， the depression model group exhibited significant depressive-like behaviors. In addition， the immunofluorescence areas of Ibal and P2RX7 in the PFC were significantly increased （P<0.01）， the levels of IL-1β and IL-18 in serum and the PFC were significantly elevated （P<0.01）， and the protein expression levels of Panx1， P2RX7， NLRP3， ASC， Caspase-1， and GSDMD in the PFC were significantly upregulated （P<0.01）. In contrast， the protein expression levels of PSD95 and Synapsin 1 were significantly downregulated （P<0.01）， and neuronal dendritic spine density was significantly reduced （P<0.01）. Compared with the model group， the Zhizi Houpotang full-formula group and the GF-MOC herbal pair group showed significant improvement in all the above indicators （P<0.01）. The GF-AFI herbal pair group improved all the above indicators except P2RX7， Caspase-1， GSDMD， and PSD95 （P<0.05， P<0.01）. In contrast， the MOC-AFI herbal pair group showed no statistically significant improvement in any of the above indicators compared with the model group. ConclusionZhizi Houpotang and its key herbal pair， GF-MOC， can effectively ameliorate CUMS-induced depressive-like behaviors in mice. Its core antidepressant mechanism may involve inhibition of P2RX7/Panx1 signaling， thereby blocking the NLRP3/GSDMD-mediated pyroptosis pathway and significantly reducing the release of inflammatory cytokines IL-1β and IL-18. Simultaneously， it upregulates the expression of synapse-related proteins PSD95 and Synapsin 1 and increases dendritic spine density， promoting the recovery of synaptic plasticity. These results suggest that GF plays a key role in the antidepressant effects of this formula， and that the compatibility of GF with MOC may represent the principal herbal pair combination responsible for its core therapeutic action.

Objective:To investigate the co-occurrence patterns of psychosocial and behavioral problems among children and to identify associated influencing factors.Methods:A multicenter cross-sectional survey was conducted in 2023. A cluster random sample of 19 176 children aged 6-16 years was recruited from middle-income areas across 10 provincial capitals and municipalities in China. Psychological and behavioral problems, including anxiety, compulsive behavior, social withdrawal, depression, somatic complaints, social problems, schizoid, delinquent behaviors, hyperactivity, sexual issues, and aggression, were assessed using the Achenbach Child Behavior Checklist parent version. Co-occurrence was defined as ≥2 concurrent problems. Children were divided into 4 groups by gender and age: boys aged 6-11 years, girls aged 6-11 years, boys aged 12-16 years, and girls aged 12-16 years. Those children who had psychosocial and behavioral problems were further categorized into the single-problem group, and the co-occurrence group based on assessment results. High-frequency co-occurrence phenotypes of children′s psychosocial and behavioral problems were identified. Demographic factors, such as parental employment, education, as well as psychosocial factors like parent-child relationship, screen time and outdoor activity, were investigated. χ 2 test was used to analyze differences between groups. Multivariate Logistic regression modeling was conducted to identify potential factors. Results:Among 14 711 children (7 501 boys, 7 210 girls) who provided effective questionnaires, the detection rates of single problem in the boys aged 6-11 years, girls aged 6-11 years, boys aged 12-16 years, and girls aged 12-16 years groups were 4.9% (171/3 461), 6.2% (193/3 120), 3.9% (158/4 040), and 5.1% (208/4 090), respectively; the detection rates of co-occurrence were 7.6% (262/3 461), 7.7% (241/3 120), 4.9% (199/4 040), and 5.7% (234/4 090), respectively. The overall detection rates of co-occurrence was higher than that of single problem ( χ2=25.47, P<0.001). Among children with co-occurrence, there were varied manifestations: in the boys aged 6-11 years group, the detection rates of social withdrawal (69.8% (183/262)), schizoid-like behavior (68.3% (179/262)), and compulsive behavior (67.6% (177/262)) were relatively high; in the girls aged 6-11 years group, the detection rates of schizoid-compulsive behavior (69.3% (167/241)), delinquent behavior (65.6% (158/241)), and hyperactivity (58.9% (142/241)) were relatively high; in the boys aged 12-16 years group, the detection rates of hyperactivity (78.9% (157/199)), compulsive behavior (67.3% (134/199)), and immature behavior (57.3% (114/199)) were relatively high; in the girls aged 12-16 years group, the detection rates of schizoid-like behavior (89.7% (210/234)), immature behavior (59.0% (138/234)), and cruelty (57.7% (135/234)) were relatively high. Maternal bachelor′s degree or higher ( OR=0.78, 95% CI 0.61-0.99, P=0.038) served as co-occurrence protective factors, whereas having 1 or more siblings, increased parent-child conflict and decreased parent-child interaction time ( OR=1.24, 1.41, 1.36; 95% CI 1.02-1.52, 1.15-1.73, 1.02-1.82, all P<0.05) were co-occurrence risk factors. Conclusions:Children exhibit strong co-occurrence tendencies in psychosocial and behavioral problems. Compulsive and schizoid traits are the predominant co-occurring phenotypes for childhood and girls respectively. ?Familial environment plays a critical role, necessitating ?multidimensional clinical assessments and ?family-centered interventions.

Objective To explore the relationship between the coagulation and fibrinolysis function in the early pregnancy and the occurrence of gestational diabetes mellitus(GDM)in women with different pre pregnancy body mass indexes(BMI).Methods 290 pregnant women undergoing the prenatal check ups at the Second Affiliated Hospital of Kunming Medical University from September 2023 to February 2024 were selected.Pre pregnancy BMI,age,family genetic history,parity,parity,and early pregnancy coagulation and fibrinolysis function test results were collected.Based on whether GDM had occurred,they were divided into GDM group(n=72)and non GDM group(n=218),and further divided into low weight GDM group(n=8),low weight non GDM group(n=29),normal weight GDM group(n=39),normal weight non GDM group(n=145),overweight/obesity GDM group(n=25),overweight/obesity non GDM group(n=44)based on pre pregnancy BMI.Basic data comparison was conducted on the total population and BMI groups.Independent sample t-test or Mann Whitney U test was used for quantitative data,and chi square test or Fisher's exact probability method was used for qualitative data.Multivariate logistic regression was used to correct the influencing factors.Results After adjusting the confounding factors such as age,family history,and pre pregnancy BMI,APTT was negatively correlated with the occurrence of GDM in the overall population(P<0.05,OR=0.840),while FIB was positively correlated with GDM(P<0.01,OR=2.598).In low body weight recombination,APTT was negatively correlated with GDM(P<0.05,OR=0.483),FIB was positively correlated with GDM(P<0.05,OR=82.501),while there was no significant correlation between APTT,FIB and GDM after adjusting the age,family history,and pre pregnancy BMI;In the normal weight group,APTT was negatively correlated with GDM(P<0.01,OR=0.786)and FIB was positively correlated with GDM(P<0.05,OR=2.413).However,after adjusting the age,family history,and pre pregnancy BMI,APTT remained negatively correlated with GDM(P<0.05,OR=0.812)and FIB remained positively correlated with GDM(P<0.05,OR=2.391);In the overweight/obese group,TT was negatively correlated with GDM(P<0.05,OR=0.510),while there was no significant correlation between TT and GDM after adjusting the age,family history,and pre pregnancy BMI.Conclusion In the normal weight population,APTT is negatively correlated with the occurrence of GDM,while FIB is positively correlated with the occurrence of GDM;In the low weight and overweight/obese populations,coagulation and fibrinolysis related indicators are greatly influenced by BMI and have no significant correlation with the occurrence of GDM.

To investigate the anti-atherosclerotic effects of dietary hesperidin and naringin on ather-osclerosis in rabbits.Twenty-four adult healthy male New Zealand Large White rabbits were ran-domly assigned to four groups based on one factor:control(Con),model(Mod),hesperidin(HP),and naringenin(NG),each containing six rabbits and housed in solitary cages.During the experi-mental period,the control group received normal feed;the model group was fed high-fat for 30 d to establish the atherosclerosis,(AS)model and continued to be fed high-fat feed;the hesperidin and naringenin groups were fed high-fat for 30 d and then underwent AS modeling,and at a later stage,150 mg of hesperidin(or naringenin)was added to the diets at a rate of 1.5 mg per kg of di-et,respectively,for 30 d.Relative body quality,blood lipids,oxidation,and inflammatory factor lev-els were all assessed.At the end of the test period,the test rabbits were sacrificed to obtain the common carotid artery for histopathological section HE staining,Oil red O staining,and Sirius red staining in order to observe vascular tissue structure,lipid and inflammatory cell infiltration,and e-lastic plate and elastic fiber damage.The results indicated that the relative body quality of the mod-el,HP and NG groups increased rapidly,and the difference with the control group within the same period was highly significant(P＜0.01);The HP and NG interventions significantly decreased to-tal cholesterol(TC)and low-density lipoprotein cholesterol(LDL-C)levels(P＜0.01),while also leading to a significant increase in high-density lipoprotein cholesterol(HDL-C)levels(P＜0.01);MDA levels exhibited a significant decrease(P＜0.01),while SOD levels showed a notable in-crease(P＜0.01)following the HP and NG interventions;After HP and NG interventions,TNF-α and IL-1 were regressed(P＜0.01)and IL-10 was significantly elevated(P＜0.01);Compared with the control group,the model group showed approximately 41.8 and 2.5 fold thickening of the maximal endo-medial membrane,respectively,and the HP and NG interventions showed approxi-mately 13 and 15 fold thickening of the maximal endo-medial membrane,and both of the maximal medial membranes thickened by approximately 1.4 fold;Staining of pathological sections showed that HP and NG intervened to significantly reduce inflammatory cell infiltration,deposition of lipid components,slight thickening of the endothelium,and intact fibroblastic components.The results showed that the addition of HP and NG to diets could regulate blood lipids and exert anti-inflam-matory and antioxidant effects by inhibiting the expression of inflammatory factors and oxidizing factors,showing significant anti-AS effects,and the two effects were comparable.

Objective:To investigate the co-occurrence patterns of psychosocial and behavioral problems among children and to identify associated influencing factors.Methods:A multicenter cross-sectional survey was conducted in 2023. A cluster random sample of 19 176 children aged 6-16 years was recruited from middle-income areas across 10 provincial capitals and municipalities in China. Psychological and behavioral problems, including anxiety, compulsive behavior, social withdrawal, depression, somatic complaints, social problems, schizoid, delinquent behaviors, hyperactivity, sexual issues, and aggression, were assessed using the Achenbach Child Behavior Checklist parent version. Co-occurrence was defined as ≥2 concurrent problems. Children were divided into 4 groups by gender and age: boys aged 6-11 years, girls aged 6-11 years, boys aged 12-16 years, and girls aged 12-16 years. Those children who had psychosocial and behavioral problems were further categorized into the single-problem group, and the co-occurrence group based on assessment results. High-frequency co-occurrence phenotypes of children′s psychosocial and behavioral problems were identified. Demographic factors, such as parental employment, education, as well as psychosocial factors like parent-child relationship, screen time and outdoor activity, were investigated. χ 2 test was used to analyze differences between groups. Multivariate Logistic regression modeling was conducted to identify potential factors. Results:Among 14 711 children (7 501 boys, 7 210 girls) who provided effective questionnaires, the detection rates of single problem in the boys aged 6-11 years, girls aged 6-11 years, boys aged 12-16 years, and girls aged 12-16 years groups were 4.9% (171/3 461), 6.2% (193/3 120), 3.9% (158/4 040), and 5.1% (208/4 090), respectively; the detection rates of co-occurrence were 7.6% (262/3 461), 7.7% (241/3 120), 4.9% (199/4 040), and 5.7% (234/4 090), respectively. The overall detection rates of co-occurrence was higher than that of single problem ( χ2=25.47, P<0.001). Among children with co-occurrence, there were varied manifestations: in the boys aged 6-11 years group, the detection rates of social withdrawal (69.8% (183/262)), schizoid-like behavior (68.3% (179/262)), and compulsive behavior (67.6% (177/262)) were relatively high; in the girls aged 6-11 years group, the detection rates of schizoid-compulsive behavior (69.3% (167/241)), delinquent behavior (65.6% (158/241)), and hyperactivity (58.9% (142/241)) were relatively high; in the boys aged 12-16 years group, the detection rates of hyperactivity (78.9% (157/199)), compulsive behavior (67.3% (134/199)), and immature behavior (57.3% (114/199)) were relatively high; in the girls aged 12-16 years group, the detection rates of schizoid-like behavior (89.7% (210/234)), immature behavior (59.0% (138/234)), and cruelty (57.7% (135/234)) were relatively high. Maternal bachelor′s degree or higher ( OR=0.78, 95% CI 0.61-0.99, P=0.038) served as co-occurrence protective factors, whereas having 1 or more siblings, increased parent-child conflict and decreased parent-child interaction time ( OR=1.24, 1.41, 1.36; 95% CI 1.02-1.52, 1.15-1.73, 1.02-1.82, all P<0.05) were co-occurrence risk factors. Conclusions:Children exhibit strong co-occurrence tendencies in psychosocial and behavioral problems. Compulsive and schizoid traits are the predominant co-occurring phenotypes for childhood and girls respectively. ?Familial environment plays a critical role, necessitating ?multidimensional clinical assessments and ?family-centered interventions.

To investigate the anti-atherosclerotic effects of dietary hesperidin and naringin on ather-osclerosis in rabbits.Twenty-four adult healthy male New Zealand Large White rabbits were ran-domly assigned to four groups based on one factor:control(Con),model(Mod),hesperidin(HP),and naringenin(NG),each containing six rabbits and housed in solitary cages.During the experi-mental period,the control group received normal feed;the model group was fed high-fat for 30 d to establish the atherosclerosis,(AS)model and continued to be fed high-fat feed;the hesperidin and naringenin groups were fed high-fat for 30 d and then underwent AS modeling,and at a later stage,150 mg of hesperidin(or naringenin)was added to the diets at a rate of 1.5 mg per kg of di-et,respectively,for 30 d.Relative body quality,blood lipids,oxidation,and inflammatory factor lev-els were all assessed.At the end of the test period,the test rabbits were sacrificed to obtain the common carotid artery for histopathological section HE staining,Oil red O staining,and Sirius red staining in order to observe vascular tissue structure,lipid and inflammatory cell infiltration,and e-lastic plate and elastic fiber damage.The results indicated that the relative body quality of the mod-el,HP and NG groups increased rapidly,and the difference with the control group within the same period was highly significant(P＜0.01);The HP and NG interventions significantly decreased to-tal cholesterol(TC)and low-density lipoprotein cholesterol(LDL-C)levels(P＜0.01),while also leading to a significant increase in high-density lipoprotein cholesterol(HDL-C)levels(P＜0.01);MDA levels exhibited a significant decrease(P＜0.01),while SOD levels showed a notable in-crease(P＜0.01)following the HP and NG interventions;After HP and NG interventions,TNF-α and IL-1 were regressed(P＜0.01)and IL-10 was significantly elevated(P＜0.01);Compared with the control group,the model group showed approximately 41.8 and 2.5 fold thickening of the maximal endo-medial membrane,respectively,and the HP and NG interventions showed approxi-mately 13 and 15 fold thickening of the maximal endo-medial membrane,and both of the maximal medial membranes thickened by approximately 1.4 fold;Staining of pathological sections showed that HP and NG intervened to significantly reduce inflammatory cell infiltration,deposition of lipid components,slight thickening of the endothelium,and intact fibroblastic components.The results showed that the addition of HP and NG to diets could regulate blood lipids and exert anti-inflam-matory and antioxidant effects by inhibiting the expression of inflammatory factors and oxidizing factors,showing significant anti-AS effects,and the two effects were comparable.

Objective:This study aimed to summarize the clinical characteristics and prognosis of patients with bone marrow invasive follicular lymphoma (FL) and discuss the treatment modalities.Methods:This study included 183 consecutive patients with FL accompanied by bone marrow invasion and receiving regular treatment at the Hospital of Hematology, Chinese Academy of Medical Sciences, from January 2013 to December 2022. Clinical data were retrospectively collected and analyzed, and single and multifactorial analyses of survival prognosis were conducted with the Kaplan-Meier method and Cox regression model.Results:The median age was 48 (range: 19 - 78) years, and the male-to-female ratio was 0.9∶1. All of the patients had bone marrow invasion, 27.8% had increased lactate dehydrogenase levels, 42.1% had lymphocyte counts of >5×10 9/L, 18.4% had abnormal chromosomal karyotypes, and 48.6% had Ki-67 index of ≥30% in lymphoid tissue. Comparison of different subgroups: lymphocyte counts of >5×10 9/L, number of lymph nodes of ≥5 involved, and proportion of bone marrow chromosomal abnormalities occurring were higher in the anthracycline-intensive treatment group than in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) protocol and the nucleoside analog (including CD20 monoclonal antibody in combination with fludarabine and bendamustine) groups (all P<0.05). The complete remission rate was 39.1% in the conventional R-CHOP group, which was lower and statistically significant than that in the intensive treatment group (55.1%) and the nucleoside analog group (62.5%) ( P=0.042). The multivariate analysis for survival analysis revealed high risk of FLIPI ( HR= 1.910, 95% CI 1.036 - 3.522, P=0.036), chromosomal abnormalities karyotype ( HR=2.666, 95% CI 1.333-5.331, P=0.006), and conventional R-CHOP treatment ( HR=2.287, 95% CI 1.140-4.591, P=0.020) were the independent adverse prognostic factors affecting progression-free survival (PFS), whereas POD24 was the only independent adverse prognostic factor affecting overall survival (OS) adverse prognostic factor ( HR=9.581, 95% CI 3.000 - 30.593, P<0.001) . Conclusions:The clinical presentations of patients with bone marrow invasive FL were easy to combine the clinical features, including increased lymphocyte count, chromosomal abnormalities, and Ki-67 index in lymphoid tissues. The FLIPI score, chromosomal abnormal karyotype, and high-lymphoid-tissue Ki-67 index were the poor prognostic factors influencing PFS. R-CHOP therapy demonstrated a poor prognosis in this group of patients.

Objective:To explore the efficacy and safety of ibrutinib for the treatment of newly treated and relapsed refractory (R/R) lymphoplasmacytic lymphoma (LPL) /Waldenstr?m macroglobulinemia (WM) .Methods:Retrospectively collected clinical data of 98 cases of newly treated and R/R LPL/WM patients who received ibrutinib treatment at the Hematology & Blood Diseases Hospital of the Chinese Academy of Medical Sciences from March 2016 to June 2023, and analyzed their efficacy and safety.Results:A total of 98 LPL/WM patients were included, which consisted of 45 newly treated patients and 53 R/R patients. Of these, 74 were males (75.5%) and the cohort had a median age of 64 (42-87) years. Eighty-eight patients were eligible for efficacy evaluation with a median treatment time of 20.8 (2.1-55.0) months, a major remission rate (MRR) of 78.4%, and an overall response rate (ORR) of 85.2%. The MRR and ORR of the newly treated patients were 78.4% and 86.5%, respectively, whereas the MRR and ORR of the R/R patients were 78.4% and 84.3%, respectively. There were no statistically significant differences in MRR and ORR between the initial treatment and R/R patients (all P values >0.05) . The median follow-up period was 29.1 (2.9-50.3) months and the median overall survival time for newly treated and R/R patients was not reached. The median progression-free survival time was 23.5 (95% CI 10.5-36.5) months and 45.0 (95% CI 34.0-56.0) months, respectively, with no statistically significant differences (all P values >0.05) . There were 25 deceased patients and no deaths were related to ibrutinib treatment. The main adverse reactions of ibrutinib were thrombocytopenia (5.1%) , pneumonia (8.1%) , and hyperuricemia (21.4%) . The incidence of atrial fibrillation was 2.0%. Conclusion:Ibrutinib exhibits good efficacy and safety for newly treated and R/R LPL/WM patients.

Purpose/Significance To construct a Chinese medical knowledge Q&A corpus dataset as a standardized evaluation bench-mark for large language models(LLMs)in the medical domain,so as to improve the accuracy and efficiency of LLMs in handling Chinese medical questions.Method/Process Chinese medical paper knowledge,medical terminology explanations and supplementary questions are acquired from the Chinese medical licensing examination,and open-source Chinese medical Q&A datasets are encompassed in the developed Q&A datasets.Result/Conclusion The Chinese medical knowledge Q&A corpus datasets enrich the sources of existing datasets and promote the objective and comprehensive quantitative evaluation of large models in the medical field.In the near future,additional data such as electronic medical records and those from online health communities will be used to strengthen the support of artificial intelli-gence for the Healthy China strategy.

Objective:To investigate serum vitamin A and vitamin D status in children aged 2-<7 years in 20 cities in China.Methods:A cross-sectional study was conducted. A total of 2 924 healthy children aged 2-<7 years were recruited from September 2018 to September 2019 from 20 cities in China, categorized by age groups of 2-<3 years, 3-<5 years, and 5-<7 years. The demographic and economic characteristics and health-related information of the enrolled children were investigated. Body weight and height were measured by professional staff members. The serum vitamin A and vitamin D levels were detected by high-performance liquid chromatography-tandem mass spectrometry. Chi-square test and Logistic regression were applied to analyze the association between vitamin A and vitamin D deficiency and insufficiency as well as their underlying impact factors.Results:The age of the 2 924 enrolled children was 4.33 (3.42, 5.17) years. There were 1 726 males (59.03%) and 1 198 females (40.97%). The prevalences of vitamin A and vitamin D deficiency in enrolled children were 2.19% (64/2 924) and 3.52% (103/2 924), respectively, and the insufficiency rates were 29.27% (856/2 924) and 22.20% (649/2 924), respectively. Children with both vitamin A and vitamin D deficiencies or insufficiencies were found in 10.50% (307/2 924) of cases. Both vitamin A ( χ2=7.91 and 8.06, both P=0.005) and vitamin D ( χ2=71.35 and 115.10, both P<0.001) insufficiency rates were higher in children aged 3-<5 and 5-<7 years than those in children aged 2-<3 years. Vitamin A and vitamin D supplementation in the last 3 months was a protective factor for vitamin A and D deficiency and insufficiency, respectively ( OR=0.68 and 0.22, 95% CI 0.49-0.95 and 0.13-0.40, both P<0.05). The rates of vitamin A and D insufficiency was higher in children with annual household incomes <60 000 RMB than in those with annual household incomes ≥60 000 RMB ( χ2=34.11 and 10.43, both P<0.01). Northwest and Southwest had the highest rates of vitamin A and vitamin D insufficiency in children aged 2-<7 yeas, respectively ( χ2=93.22 and 202.54, both P<0.001). Conclusions:Among 20 cities in China, children aged 2-<7 years experience high rates of vitamin A and vitamin D insufficiency, which are affected by age, family economic level, vitamin A and vitamin D supplementation, and regional economic level. The current results suggest that high level of attention should be paid to vitamin A and vitamin D nutritional status of preschool children.