[Effects of residual paralysis after a single intubating dose of rocuronium on postoperative pulmonary function of patients undergoing laparoscopic gynecological surgeries].

OBJECTIVE: To evaluate the residual paralysis after a single intubating dose of rocuronium and its effect of residual paralysis after a single dose of rocuronium on the postoperative pulmonary function of patients undergoing laparoscopic gynecological surgeries. METHODS: Sixty American Society of Anesthesiologists (ASA) I - II patients undergoing laparoscopic gynecological surgeries were randomly divided into rocuronium (R) group (n = 30) and rocuronium + neostigmine (R + N) group (n = 30).All patients received midazolam (0.02 mg/kg), fentanyl (1 microg/kg), propofol(1.5-2 mg/kg), and rocuronium (0.6 mg/kg) to facilitate tracheal intubation and no more relaxant thereafter. Anesthesia was maintained with isoflurane and nitrous oxide in oxygen (N(2)O:O(2) = 1:1). At the end of the procedure, neuromuscular blockade was not reversed in R group, while antagonism was accomplished with neostigmine (0.04 mg/kg) and atropine (0.02 mg/kg) in R + N group. Immediately after tracheal extubation and on arrival in the PACU, the train-of-four (TOF) ratio at the adductor pollicis of all patients were measured using acceleromyography. Forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), and peak expiratory flow rate (PEFR) of all patients were measured using spirometry before surgery, after administration of midazolam and fentanyl, immediately after tracheal extubation, on arrival in the PACU, and after the TOF ratio recovered to 1.0. The TOF ratio and pulmonary function between two groups were compared. RESULTS: Immediately after tracheal extubation and on arrival in the PACU, the mean TOF ratio in R group was significantly lower than that in R + N group (P < 0.05). The mean time to achieve TOF ratio of 0.9 and 1.0 in R group was significantly longer than in R + N group (P < 0.05). Immediately after tracheal extubation and on arrival in the PACU, FVC, FEV(1), and PEFR were significantly lower in R group than in R + N group (P < 0.05). FVC, FEV(1), and PEFR after administration of midazolam and fentanyl and after TOF ratio recovered to 1.0 were significantly lower than the baseline values in all patients (P < 0.01). CONCLUSIONS: After a single intubating dose of rocuronium, residual paralysis exists in the majority of patients undergoing laparoscopic gynecological surgeries. The pulmonary function is impaired after the surgery, even after recovery of TOF ratio to 1.0.

[Effects of melatonin on the voltage-gated delayed rectifier potassium channels of cultured hippocampal neurons of new-born rats].

OBJECTIVE: To investigate the effects of melatonin on voltage-gated delayed rectifier potassium channels. METHODS: Hippocampus neurons were obtained from newborn Wistar rat and cultured. Primary cultured for 7 to 12 days of new-born Wistar rat were selected as objectives. Patch clamp whole-cell recording technique was used on the hippocampus neurons cultured for 7 to 12 day. to record the delayed rectifier potassium current to analyze the basic electrophysiological characteristics. The effects of melatonin of the concentrations of 1 nmol/L, 10 nmol/L, 100 nmol/L, 1 mol/L, 10 mol/L, 100 mol/L, and 1 mmol/L on the amplitudes and kinetics of delayed rectifier potassium currents were investigated. RESULTS: With different voltage protocols and specific blockers of potassium channel (4-AP and TEA) a delayed rectifier potassium current that activated and inactivated slowly and had the outward rectifying characteristics (Ik) from the outward potassium currents in cultured new-born hippocampus neurons was separated. The effect of melatonin on the delayed rectifier channel was rapid, reversible and voltage-dependent Melatonin had no effect on the kinetic characteristics of the I -V curve. Melatonin increased the potassium current concentration-dependently. 1 - 100 nmol/L melatonin increased the amplitude of potassium current gradually; the effects of 1 - 100 micromol/L melatonin on the potassium current increased concentration-dependently, while the action of 1 mmol/L melatonin decreased. CONCLUSION: Melatonin reversibly increases the rectifier delayed potassium currents of the cultured hippocampus neurons of new-born rat. This may be involved in some aspects of physiological and pathological significance of potassium currents.

[Protective endotracheal intubation to reduce endotracheal bacterial contamination].

OBJECTIVE: To initially observe the effect of classical endotracheal intubation on endotracheal bacterial contamination and evaluate the validity of protective endotracheal intubation on reducing endotracheal bacterial contamination. METHODS: Ninety elective patients undergoing general anesthesia for hysterectomy were randomly assigned to two equal groups. Group II received endotracheal intubation protected by sterilized transparent sleeve while group I correspondingly adopted unprotective classical endotracheal intubation. Endotracheal swab sampling and bacterial counting were performed on the principle of aseptic processing before endotracheal intubation and extubation, respectively. RESULTS: Bacteria were found in 62 of 180 samples. The difference of bacterial counting between before extubation and before intubation was (-0.3 +/- 35.6) 100 CFU/ ml in group II, lower than that in group I, which was (21.4 +/- 56.7) 100 CFU/ml (P<0.05). CONCLUSION: Endotracheal bacterial contamination may be caused by unprotective classical endotracheal intubation and could be reduced by protective endotracheal intubation.

Malignant hyperthermia in China.

Malignant hyperthermia has rarely been reported in China. We report the first case of malignant hyperthermia, verified by caffeine-halothane contracture test and genetic testing, in a Chinese patient.

Changes of interleukin-6 and related factors as well as gastric intramucosal pH during colorectal and orthopaedic surgical procedures.

OBJECTIVE: To investigate the changes of perioperative serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and cortisol, as well as gastric intramucosal pH (pHi) and plasma lactate, aiming to compare systemic changes and tissue perfusion during colorectal and orthopaedic surgical procedures. METHODS: Twenty patients were randomly assigned to two groups, 10 cases of operation on vertebral canal, 10 cases of colorectal radical operation. Venous blood was drawn at 1 day before operation, 2, 4, and 6 hours following skin incision, and 1 day after operation, in order to measure serum IL-6, CRP, and cortisol. pHi and plasma lactate were also measured at the same time points. RESULTS: Serum concentrations of IL-6 and cortisol increased gradually following operation, reaching the peak value at 6 hours from the beginning of operation. CRP was not detectable until the first day after operation. Peak concentration of IL-6 had positive relationship with CRP. These variables changed more significantly in colorectal group than that in orthopaedic group (P < 0.05). pHi decreased gradually, reaching the lowest level at 4 hours from the beginning of operation, and to more extent in colorectal group than that in orthopaedic group (P < 0.05). CONCLUSION: IL-6 may reflect tissue damage more sensitively than CRP. Colorectal surgery might induce systemic disorder to more extent, in terms of immuno-endocrinal aspect as well as tissue perfusion, reflected with pHi.

[Perioperative cortisol circadian secretion and neuropsychological states in patients undergoing coronary artery bypass grafting surgery].

OBJECTIVE: To investigate the relationship between the circadian rhythm of perioperative cortisol secretion and neuropsychological states in patients undergoing coronary artery bypass grafting surgery. METHODS: Forty male patients scheduled for elective coronary artery bypass grafting (CABG) under hypothermic cardio-pulmonary bypass (CPB) or off-pump were enrolled in this study. They were allocated into CPB group or off-pump group with 20 patients in each group. Blood samples were withdrawn during surgery at specific time-points and every 3 h for 24 h in the immediate postoperative period. Plasma cortisol was measured by radioimmunoassay. All subjects were investigated preoperatively as well as 7 to 10 d and 3 months postoperatively with a comprehensive neuropsychologic assessment, while depression and anxiety were assessed by Self-Rating Depression Scale and the State-Trait Anxiety Inventory respectively. RESULTS: During postoperative 24 h, three patients in the CPB group and 7 patients in the off-pump group were demonstrating a circadian secretion pattern, while they were disturbed in the remaining patients in both groups. Postoperative depression scores of patients in both groups were significantly higher than preoperative values. Postoperative anxiety scores of patients in the CPB group were significantly higher than those in the off-pump group. The CABG with CPB patients showed a significant deficit in the Digit Span subtest of the WAIS-R and the Stroop colour word interference test. The disturbed cortisol circadian secretion in the CPB group correlated with depression and the Stroop colour word interference test, whereas in the off-pump group it correlated with depression, Digit Span subtest (forward), symbol digit modalities test and the Stroop colour word interference test. Degree of depression correlated with some items of cognitive dysfunctions. CONCLUSION: Perioperative secretion rhythm of cortisol in patients undergoing CABG surgery with CPB or off-pump was disturbed. The disordered cortisol may correlate directly or indirectly through mood with neuropsychological deficits.

[Effect of intraoperative using cell saver on blood sparing and its impact on coagulation function].

OBJECTIVE: To observe the effectiveness of using cell saver (CS) during surgery on blood sparing and its impact on patient's hematology and coagulation function. METHODS: One-hundred and thirty-eight patients undergoing elective surgery were recruited for intraoperative blood salvage using CS. Blood routine, blood chemistry and coagulation function were measured before surgery, after infusion of salvaged blood and postoperative day 1, respectively. RESULTS: In total, 112,056 ml of packed red blood cells were collected, with a mean value of 812 ml per patient. The percentage of autologous blood transfusion volume to the total blood transfusion volume was from 48% to 89%. Allogenic blood transfusion rate was from 5% to 100%. Compared with the values before surgery, the hemoglobin concentration, platelet count, plasma total protein and fibrinogen concentration decreased significantly after the transfusion of salvaged blood and the first postoperative day (P < 0.05 or P < 0.01), while the prothrombin time was significantly prolonged (P < 0.05). CONCLUSIONS: The use of CS during surgery can, to a certain extent, reduce the requirement of allogenic blood. However, reinfusion of large amount of salvaged blood may affect coagulation function.

[Perioperative melatonin circadian secretion in patients undergoing coronary artery bypass grafting surgery].

OBJECTIVE: To investigate the circadian rhythm of perioperative melatonin secretion in patients undergoing coronary artery bypass grafting surgery. METHODS: Forty male patients scheduled for elective coronary artery bypass grafting surgery (CABG) under hypothermic cardiopulmonary bypass (CPB) or off-pump were allocated into two groups of 20 patients: CPB group and off-pump group. Blood samples were withdrawn from all patients immediately before the induction of anesthesia (baseline), 10 min after the induction of anesthesia, 10 min after heparinization, 30 min after commencement of CPB (or 2h after skin incision), before reversal of heparin with protamine, at the end of surgery, and. every 3 hours after operation until the twenty-fourth hour. The plasma concentration of melatonin was measured by using enzyme-linked immunosorbent assay. RESULTS: The plasma melatonin concentrations during and after CPB were higher than the baseline value in the CPB group. There were no differences in the melatonin concentrations in the off-pump group. In the CPB group the melatonin concentrations after induction, during CPB, and after CPB were 7.2 +/- 3.4, 10.5 +/- 5.2, and 9.5 +/- 4.0 respectively, all significantly higher than those in the off-pump (5.5 +/- 2.5, 6.3 +/- 2.0, and 5.7 +/- 2.1 respectively, all P < 0.05). During the twenty-four hours after operation, two patients in the CPB group and six patients in the off-pump group showed circadian rhythm of melatonin secretion. CONCLUSION: The perioperative circadian rhythm of melatonin secretion in patients undergoing CABG surgery with CPB or off-pump is disturbed, however relatively more patients under off-pump group regain secretion rhythm of melatonin in the immediate postoperative period. CPB may be one of the reasons for perioperative melatonin circadian secretion disturbance.

[Remifentanil for intraoperative anesthesia].

OBJECTIVE: To compare the efficacy and safety of remifentanil with fentanyl used for intraoperative anesthesia. METHODS: Fifty-four patients undergoing modified radical mastectomy or total hysterectomy were randomly assigned to remifentanil group or fentanyl group with 27 cases in each group. Anesthesia was induced with propofol (2 mg/kg) and either remifentanil (2 micrograms/kg) or fentanyl (2.5 micrograms/kg), and was maintained with inhalation of nitrous oxide in oxygen (2:1) and a continuous infusion of either remifentanil (0.2 microgram.kg-1.min-1) or fentanyl (0.03 microgram.kg-1.min-1). Depth of anesthesia, hemodynamic changes, recovery profile of anesthesia, postoperative analgesia and adverse reactions were observed. RESULTS: The number of patients exhibited light depth of anesthesia during tracheal intubation and maintenance in the remifentanil group was significantly fewer than that in the fentanyl group (P < 0.05). Hemodynamic changes during intubation, skin incision, maintenance of anesthesia and extubation in the remifentanil group were significantly smaller than those in the fentanyl group (P < 0.05, P < 0.01). The time to opening eyes on command and the time for extubation after surgery were comparable between the two groups. More patients in the remifentanil group required bolus injection of morphine for postoperative pain relief than those in the fentanyl group (P < 0.05). There was no significant difference between the two groups in the aspect of adverse reactions. CONCLUSION: The anesthetic and analgesic effects of remifentanil are more potent than those of fentanyl. Remifentanil can offer superior intraoperative hemodynamic stability compared with fentanyl without compromising recovery from anesthesia.

[Use of blood salvage machine in oncologic surgeries: a clinical observation of 13 cases].

OBJECTIVE: To evaluate the effects on blood sparing and risk of hematogenous tumor dissemination of the use of blood salvage machine in oncologic surgeries. METHODS: The clinical data of 13 patients, 6 with malignant tumors and 7 with benign tumors, who received the use of blood salvage machine during oncologic surgeries based on informed consent, were analyzed. RESULTS: In total 42,575 ml of packed red blood cells were collected during surgery with a mean value of 3 275 ml (400 - 1500 ml) per patient. The average amount of allogenic transfusion per patient was 1 530 ml (0 - 8,000 ml). The number of blood salvage machine use in oncologic surgeries accounted for 8.6% (13/152) of the total number of blood salvage machine use in surgeries in that period. The perioperative mortality rate of the oncologic surgeries with the use of blood salvage machine was 7.7% (1/13). The post-operative metastasis rate of liver and lung was 15.4% (2/13). CONCLUSION: The use of blood salvage machine during oncologic surgeries improves the blood sparing effect. However, it cannot be used routinely, since it may result in hematogenous tumor cell dissemination.

Concentrations of propofol in cerebral spinal fluid: target-controlled infusion.

BACKGROUND: Although the performance of target-controlled infusion (TCI) have been studied extensively, the accuracy and safety of a TCI system that targets the effect site remains to be demonstrated. This study was to investigate the relations of TCI of propofol to its concentrations in cerebral spinal fluid (CSF), the effect-site concentrations and bispectral index (BIS). METHODS: Twelve mongrel dogs were used for investigations. The target effect-site concentration was set at 3 microg/ml and the infusion was lasted for 15 minutes. CSF and blood samples were then collected and propofol concentrations were determined by using high performance liquid chromatography with fluorescence detection. BIS and hemodynamic data were monitored continuously. RESULTS: The predicted plasma concentrations were generally overestimated. Median performance error (MDPE) and absolute median performance error (MDAPE) were -10.0% and 29.9% respectively. Propofol CSF concentrations were much lower than its effect-site concentrations. Changes in BIS were consistent with propofol concentrations in CSF, both of which changed direction at 5 minutes while the effect-site concentrations relatively lagged behind. Better correlation (r(2) = 0.9195) was found between BIS and CSF concentrations, when compared with that between BIS and effect-site concentrations (r(2) = 0.554). CONCLUSION: With 1% enflurane inhaled, the inconsistency of drug effect to the effect-site concentrations may result from inaccuracy of pharmacokinetic parameters. CSF may show effect-site concentrations more accurately than plasma when using target effect-site concentration infusion.

[Comparison of preemptive analgesia efficacy between etoricoxib and rofecoxib in ambulatory gynecological surgery].

OBJECTIVE: To compare the preemptive analgesia efficacy between two cycloxygenase-2 inhibitors, rofecoxib and etoricoxib in the ambulatory uterine evacuation patients. METHODS: In this randomized, double-blinded, placebo-controlled trial 60 patients were randomly divided into three groups and received a single dose of placebo, rofecoxib 50 mg, or etoricoxib 120 mg, respectively, before operation. Patient's visual analogue score (VAS) was rated postoperatively at 15 min, 30 min, 60 min, time-to-discharge, 6 h and 24 h. Fentanyl (in post-anesthesia care unit) and paracetamol (at home) were supplementary analgesics and the dosage was also recorded. Patient's satisfaction score was rated at 24 h postoperatively. RESULTS: Etoricoxib 120 mg and rofecoxib 50 mg were significantly superior to placebo at 6 h postoperatively (P < 0.05) while there was no significant differences of VAS at other time points. The amounts of Fentanyl used in post-anesthesia care unit were similar in three groups, but paracetamol taken at home was much less in rofecoxib group and etoricoxib group than in placebo group (P < 0.01). Compared to rofecoxib, etoricoxib provided better pain relief after discharge (P < 0.05). The overall pain management satisfaction score was significantly higher in etoricoxib group (96 +/- 7) than in other groups (P < 0.01). CONCLUSION: Preemptive rofecoxib 50 mg and etoricoxib 120 mg may significantly decrease VAS at 6 h postoperatively, and reduce the usage of analgesics in ambulatory uterine evacuation patients. Etoricoxib 120 mg offeres better pain relief at home compared with rofecoxib 50 mg.

[Evaluation of tracheal intubation in critical SARS patients].

OBJECTIVE: To analyze tracheal intubation and respiratory treatment in the critical severe acute respiratory syndrome (SARS) patients. METHODS: Review and analyze tracheal intubation and respiratory treatment in critical SARS patients in intensive care unit (ICU). RESULTS: Three of thirteen patients had been intubated or received tracheotomy before they entered into ICU, the other patients received treatment of nasal cannula or oxygen mask. With the development of the disease, two patients had been intubated because of respiratory failure or tracheotomy. Tracheal intubation was twice made in two patients in order to replace tracheal tubes. CONCLUSIONS: The patient should be intubated or received tracheotomy if non-invasive respiratory support has no effect. Standard protection could protect medical staff from infection under tracheal intubation.

[Perioperative melatonin secretion rhyme in patients undergoing coronary artery bypass grafting surgery].

OBJECTIVE: To investigate perioperative patterns of melatonin and cortisol secretion rhyme in patients undergoing coronary artery bypass grafting surgery. METHODS: Eleven male patients scheduled for elective coronary artery bypass grafting surgery (CABG) under hypothermic cardiopulmonary bypass (CPB) were enrolled in the study. Anesthesia was induced and maintained with propofol (3 mg.kg-1.h-1) and supplemented with fentanyl (15 micrograms/kg). Blood samples were taken during surgery at specific time-points and every 3 h in the immediate postoperative period and postoperative day 2 and day 3. Plasma melatonin and cortisol levels were measured by radioimmunoassay and enzyme-linked immunosorbent assay respectively. RESULTS: During surgery, plasma melatonin levels were below the minimum sensitivity level but low levels, without circadian variation, were measured during the immediate postoperative period. During postoperative day 2 and day 3, circadian secretion patterns of melatonin were present in 10 patients and showed an inverse correlation with light intensity exposed (r = -0.480, P = 0.01). Plasma cortisol levels in the immediate postoperative period were significantly higher than those before induction of anesthesia (P < 0.01). During postoperative day 2 and day 3, only 3 patients regained circadian secretion of cortisol. CONCLUSIONS: It is concluded that melatonin and cortisol secretion are disrupted during cardiac surgery and in the immediate postoperative period.

[Influence of obesity on pharmacokinetics and pharmacodynamics of isoflurane].

OBJECTIVE: To observe the effect of obesity on pharmacokinetics and pharmacodynamics of isoflurane. METHODS: Twenty-six patients undergoing cholecystectomy were divided into obese group (Group A, BMI > or = 27, n = 13) and normal body weight group (Group N, BMI < or = 24, n = 13) according to body mass index (BMI). All patients were given to the same isoflurane anesthesia. Inspired and end-expired concentrations of isoflurane were monitored and uptake fraction of isoflurane were calculated. RESULTS: Isoflurane concentrations of vaporizer in Group A [(1.8 +/- 0.3)%] were evidently higher than those in Group N [(1.5 +/- 0.1)%] at all observed points (P < 0.05 or P < 0.01). Uptake fraction of isoflurane in Group A were higher than those in Group N at observed points (P < 0.05, P < 0.01 or P < 0.001), but there were no differences in the time when isoflurane concentration was lowered to 50% and awake time between the two groups after discontinuing inhaling isoflurane. CONCLUSIONS: Obese patients demand higher inspired concentration and uptake of isoflurane than those in normal weight patients but discharge of isoflurane was influenced by obesity within the observed period of (66 +/- 33) min.

[Effect of volume replacement with hydroxyethyl starch solution for blood loss on splanchnic oxygenation in patients undergoing cytoreductive surgery for ovarian carcinoma].

OBJECTIVE: To investigate the effect of medium molecular weight hydroxyethyl starch solution (HES) administered as replacement for estimated blood losses (EBL) during cytoreductive surgery for ovarian carcinoma on splanchnic oxygenation. METHODS: Cytoreductive surgery was operated upon forty-two patients with ovarian carcinoma. As soon as the EBL was higher than 10% but less than 20% of the estimated blood volume, the patients were randomly assigned to receive a volume of lactated Ringer's solution (LRS) equal to three times the EBL (LRS group, n = 22) or a volume of 6% HES equal to the EBL (HES group, n = 20). Tissue oxygenation was assessed indirectly by measuring the tonometric parameters of stomach, including difference between gastric intramucosal PsCO(2) and arterial PaCO(2) (Ps-aCO(2) gap), gastric intramucosal pH (pHi) and arterial lactate acid concentration 30 min after induction of anesthesia (baseline value), 1 h and 2 h after skin incision, and at the end of surgery. RESULTS: At the end of surgery, the Ps-aCO(2) gap was 8.7 mm Hg +/- 1.6 mm Hg in the HES group, significantly lower than that in the LRS group (18.74 mm Hg +/- 4.4 mm Hg, P < 0.01), while the pHi in the HES group was 7.30 +/- 0.05, significantly higher than that in the LRS group (7.21 +/- 0.07, P < 0.01). There was no significant difference in arterial lactate acid concentration between the two groups. CONCLUSION: In patients undergoing major surgery, volume resuscitation with medium molecular weight HES improves the splanchnic blood flow and tissue oxygenation.

[Patient-controlled analgesia with tramadol and tramadol/droperidol mixture after abdominal hysterectomy: a double-blinded, randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy and side effects of tramadol and the mixture of tramadol and droperidol for postoperative patient-controlled analgesia (PCA). METHODS: Sixty female patients, aged 18 - 65, scheduled for elective abdominal total hysterectomy with inhalational general anesthesia (induced with fentanyl and propofol, maintained with O(2)-N(2)O and enflurane or isoflurane supplemented by intermittent iv fentanyl and vercuronium for muscle relaxation) were allocated into 2 groups of 30 patients in a random and double blind manner: group 1 (20 mg tramadol) and group 2 (20 mg tramadol plus 0.1 mg droperidol), both with a lockout time of 10 minutes. The VAS, analgesic doses, and side effects were observed 4, 8, 12, 20, 28, and 36 hours after operation respectively. RESULTS: Adequate analgesia was achieved with tramadol or the mixture of tramadol and droperidol. The nausea rates and vomiting rates at any time point in the group 2 were all significantly lower than those in the group 1 (all P < 0.05). Ten patients in the group 1 needed treatment of metoclopramide, and none of patients in the group 2 needed antiemetic (P < 0.01). No significant differences were observed in VAS, sedation score or vital signs (all P > 0.05). CONCLUSION: Providing a similar quality of analgesia with less nausea and vomiting as well as little need for sedative, the combination of tramadol and droperidol is superior to tramadol alone for post-operative PCA.

[Perioperative anesthetic management for the excision of phaeochromocytoma complicated with catecholamine cardiomyopathy].

OBJECTIVE: To summarize experience of perioperative anesthetic management for patients undergone excision of pheochromocytoma and complicated with catecholamine cardiomyopathy. METHODS: Perioperative anesthetic management for surgical treatment of three cases of pheochromocytoma complicated with catecholamine cardiomyopathy was described and discussed according to literature reports. RESULTS: The catecholamine cardiomyopathy of the three cases presented with left ventricular hypertrophy, congestive cardiac failure and acute myocardial infarction. After removal of the pheochromocytoma under general anesthesia, a prolonged hypotension occurred in all of the three cases. In order to maintain stable hemodynamics, large dose of catecholamine was required after surgery. All of the three patients were survived and discharged. CONCLUSIONS: It is suggested that myocardial dysfunction may be another important factor for the prolonged hypotension after removal of the tumor. Meticulous preoperative assessment of heart function is of primary importance for the management of anaesthesia during surgical procedures.