CONTEXT: The incidence of tendon injuries and tendinopathy has risen substantially in the past decades. OBJECTIVE: To assess the noninferiority of therapy based on the homeopathic preparation Traumeel S ointment (Heel GmbH, Baden-Baden, Germany) compared with treatment based on diclofenac 1% gel in patients with tendinopathies of varying etiology. DESIGN: Nonrandomized, observational study. SETTING: Ninety-five homeopathy and conventional medical practices in Germany. PATIENTS: Three hundred fifty-seven patients aged 18 to 93 years with tendinopathy of varying etiology based on excessive tendon load rather than inflammation. INTERVENTIONS: Traumeel S ointment or diclofenac 1% gel for a maximum of 28 days. MAIN OUTCOME MEASURES: Efficacy was measured on a four-degree scale on pain-related variables, on variables related to motility, and on overall treatment outcome. Tolerability was monitored as adverse events. Compliance was assessed by practitioner and patient on a four-degree scale. RESULTS: The patients groups were comparable at baseline. The changes in summary score of all pain-related variables were -5.3 +/- 2.7 (all values means +/- SD) in the Traumeel group and -5.0 +/- 2.7 in the control group. Changes for all motility-related variables were -4.2 +/- 3.8 with Traumeel and -3.7 +/- 3.4 with control therapy. The summary scores for all clinical variables were reduced by -9.5 +/- 5.7 with Traumeel therapy and by -8.7 +/- 5.4 with diclofenac-based treatment. Homeopathic therapy was noninferior to diclofenac therapy on all variables. For motility-related variables, there was a trend toward superiority of Traumeel. Treatments were well tolerated with no treatment-related adverse events. CONCLUSIONS: The results suggest that Traumeel ointment is an effective alternative to nonsteroidal antiinflammatory drugs therapy for the acute symptomatic treatment of patients with tendinopathy.

OBJECTIVE:: To evaluate the efficacy and safety of a homeopathic gel vs an NSAID (piroxicam) gel in the treatment of osteoarthritis of the knee.

METHOD:: One hundred and eighty-four out-patients with radiographically confirmed symptomatic osteoarthritis of the knee were entered into a pragmatic, randomized, double-blind controlled trial and treated with 1 g of gel three times daily for 4 weeks. Main outcome measures were pain on walking as a Visual Analogue Score (VAS) and a single-joint Ritchie index.

RESULTS:: One hundred and seventy-two of the 184 enrolled patients had endpoints for the main outcome parameters. The pain reduction was 16.5 mm VAS in the homeopathy group (n = 86) and 8.1 mm in the piroxicam group (n = 86); the difference between treatment groups was 8.4 mm (95% confidence interval 0.8-15.9), and after adjustment for pain at baseline it was 6.8 mm (95% confidence interval -0.3 to 13.8). There was no significant difference between treatment groups in the single-joint Ritchie index (P = 0.78). Adverse events occurred in 28 patients (12 homeopathy group, 5 withdrawn; 16 piroxicam group, 9 withdrawn); 18 of the events involved a local reaction (7 homeopathy group, 2 withdrawn; 11 piroxicam group, 5 withdrawn).

CONCLUSION:: The homeopathic gel was at least as effective and as well tolerated as the NSAID gel. The presence of a clinically relevant difference between treatment groups cannot be excluded. The homeopathic gel supplemented by simple analgesics if required may provide a useful treatment option for patients with osteoarthritis.

OBJECTIVES: To investigate the efficacy of acupuncture compared with steroid treatment in patients with mild-to-moderate carpal tunnel syndrome (CTS) as measured by objective changes in nerve conduction studies (NCS) and subjective symptoms assessment in a randomized, controlled study. METHODS: A total of 77 consecutive and prospective CTS patients confirmed by NCS were enrolled in the study. Those who had fixed sensory complaint over the median nerve and thenar muscle atrophy were excluded. The CTS patients were randomly divided into 2 treatment arms: (1) 2 weeks of prednisolone 20 mg daily followed by 2 weeks of prednisolone 10 mg daily (n = 39), and (2) acupuncture administered in 8 sessions over 4 weeks (n = 38). A validated standard questionnaire as a subjective measurement was used to rate the 5 major symptoms (pain, numbness, paresthesia, weakness/clumsiness, and nocturnal awakening) on a scale from 0 (no symptoms) to 10 (very severe). The total score in each of the 5 categories was termed the global symptom score (GSS). Patients completed standard questionnaires at baseline and 2 and 4 weeks later. The changes in GSS were analyzed to evaluate the statistical significance. NCS were performed at baseline and repeated at the end of the study to assess improvement. All main analyses used intent-to-treat. RESULTS: A total of 77 patients who fulfilled the criteria for mild-to-moderate CTS were recruited in the study. There were 38 in the acupuncture group and 39 in the steroid group. The evaluation of GSS showed that there was a high percentage of improvement in both groups at weeks 2 and 4 (P < 0.01), though statistical significance was not demonstrated between the 2 groups (P = 0.15). Of the 5 main symptoms scores (pain, numbness, paresthesia, weakness/clumsiness, nocturnal awakening), only 1, nocturnal awakening, showed a significant decrease in acupuncture compared with the steroid group at week 4 (P = 0.03). Patients with acupuncture treatment had a significant decrease in distal motor latency compared with the steroid group at week 4 (P = 0.012). Acupuncture was well tolerated with minimal adverse effects. CONCLUSIONS: Short-term acupuncture treatment is as effective as short-term low-dose prednisolone for mild-to-moderate CTS. For those who do have an intolerance or contraindication for oral steroid or for those who do not opt for early surgery, acupuncture treatment provides an alternative choice.

Because five-year survival rates for patients with metastatic melanoma remain below 25%, there is continued need for new therapeutic approaches. For some tumors, pharmacologic ascorbate treatment may have a beneficial antitumor effect and may work synergistically with standard chemotherapeutics. To investigate this possibility in melanoma, we examined the effect of pharmacologic ascorbate on B16-F10 cells. Murine models were employed to compare tumor size following treatment with ascorbate, and the chemotherapeutic agents dacarbazine or valproic acid, alone or in combination with ascorbate. Results indicated that nearly all melanoma cell lines were susceptible to ascorbate-mediated cytotoxicity. Compared to saline controls, pharmacologic ascorbate decreased tumor size in both C57BL/6 (p<.0001) and NOD-scid tumor bearing mice (p<.0001). Pharmacologic ascorbate was superior or equivalent to dacarbazine as an antitumor agent. Synergy was not apparent when ascorbate was combined with either dacarbazine or valproic acid; the latter combination may have additional toxicities. Pharmacologic ascorbate induced DNA damage in melanoma cells, as evidenced by increased phosphorylation of the histone variant, H2A.X. Differences were not evident in tumor samples from C57BL/6 mice treated with pharmacologic ascorbate compared to tumors from saline-treated controls. Together, these results suggest that pharmacologic ascorbate has a cytotoxic effect against melanoma that is largely independent of lymphocytic immune functions and that continued investigation of pharmacologic ascorbate in cancer treatment is warranted.

BACKGROUND:The homeopathic preparation of Pulsatilla nigricans is used in the treatment of anxiety related disorders. Though in clinical use for many years, the anxiolytic activity of Pulsatilla nigricans (Puls) has not been evaluated experimentally. Hence the present study was conducted in Swiss albino mice to evaluate the anxiolytic activity of Puls and compare its activity with the standard anxiolytic drug, diazepam.

METHODS:Twenty four mice were divided into 4 groups of 6 animals each, control, standard and two test groups. The control group was treated Ethyl alcohol 10ml/kg. The standard group received Diazepam, 1mg/kg. Puls 3x and 6x solutions were given at the dose of 10ml/kg to the test groups. All animals were given the test and control treatments orally for 15 days. The anxiolytic effect was tested on days 1, 8 and 15 using the Elevated Plus Maze (EPM) and Open Field Test (OFT).

RESULTS:Both diazepam and Puls showed significant anxiolytic activity in EPM and OFT test compared to control. The total number of entries and time spent in open arm in EPM was increased by both diazepam and Puls, the effect of 3x dilution of Puls was greater than diazepam. In the OFT the number of squares crossed, rearing and assisted rearings decreased with both diazepam and Puls compared to control and the anxiolytic effect of diazepam was greater than Puls. The anxiolytic effect is greater for the 3x dilution than 6x dilution of Puls.

CONCLUSION:The study showed an anxiolytic effect of homeopathic preparation of Pulsatilla nigricans comparable to that found with a standard drug.

INTRODUCTION:Cannabidiol (CBD) containing products are available in a plethora of flavors including oral, sublingual, and inhalable forms. Immunotoxicological effects of CBD containing liquids were assessed by hypothesizing that CBD regulates oxidative stress and lipopolysaccharide (LPS) induced inflammatory responses in macrophages, epithelial cells, and fibroblasts.

METHODS:Epithelial cells (BEAS-2B and NHBE), macrophages (U937), and lung fibroblast cells (HFL-1) were treated with varying CBD concentrations or exposed to CBD aerosols and reactive oxygen species (ROS), and the inflammatory mediators, were measured. Furthermore, monocytes and epithelial cells were stimulated with LPS in combination with CBD or dexamethasone to understand the anti-inflammatory effects of CBD.

RESULTS:CBD showed differential effects on IL-8 and MCP-1, and acellular and cellular ROS levels. CBD significantly attenuated LPS-induced NF-κB activity and IL-8 and MCP-1 release from macrophages. Cytokine array data depicted a differential cytokine response due to CBD. Inflammatory mediators, IL-8, serpin E1, CXCL1, IL-6, MIF, IFN-γ, MCP-1, RANTES, and TNF-α were induced, whereas MCP-1/CCL2, CCL5, eotaxin, IL-1ra, and IL-2 were reduced. CBD and dexamethasone treatments reduced the IL-8 level induced by LPS when the cells were treated individually, but showed antagonistic effects when used in combination via MCPIP (monocytic chemotactic protein-induced protein).

CONCLUSION:CBD differentially regulated basal pro-inflammatory response and attenuated both LPS-induced cytokine release and NF-κB activity in monocytes, similar to dexamethasone. Thus, CBD has a differential inflammatory response and acts as an anti-inflammatory agent in pro-inflammatory conditions but acts as an antagonist with steroids, overriding the anti-inflammatory potential of steroids when used in combination.

OBJECTIVE: To determine the benefit of cetylated fatty acids (CFA) on knee range of motion and function in patients with osteoarthritis (OA). METHODS: Sixty-four patients with chronic knee OA were evaluated at baseline and at 30 and 68 days after consuming either placebo (vegetable oil; n = 31) or CFA (Celadrin; n = 33). Evaluations included physician assessment, knee range of motion with goniometry, and the Lequesne Algofunctional Index (LAI). RESULTS: After 68 days, patients treated with CFA exhibited significant (p < 0.001) increase in knee flexion (10.1 degrees) compared to patients given placebo (1.1 degrees). Neither group reported improvement in knee extension. Patient responses to the LAI indicated a significant (p < 0.001) shift towards functional improvement for the CFA group (-5.4 points) after 68 days compared to a modest improvement in the placebo group (-2.1 points). CONCLUSION: Compared to placebo, CFA provides an improvement in knee range of motion and overall function in patients with OA of the knee. CFA may be an alternative to the use of nonsteroidal antiinflammatory drugs for the treatment of OA.

BACKGROUND:Oil pulling therapy has been used extensively as a traditional Indian folk remedy for many years for strengthening teeth, gums, and jaws and to prevent decay, oral malodor, bleeding gums and dryness of throat, and cracked lips.

AIMS:The aims of this study were to evaluate the effect of oil pulling with sesame oil on halitosis and the microorganisms that could be responsible for it and to compare its efficacy with chlorhexidine mouthwash.

MATERIALS AND METHODS:Group I (oil pulling) and group II (chlorhexidine) included 10 adolescents each. The following parameters were assessed: marginal gingival index, plaque index, organoleptic breath assessment (ORG 1), self-assessment of breath (ORG 2), and BANA test from tongue coating samples on days 0 and 14 of the experimental period.

RESULTS:The comparisons of the pre and post therapy values of plaque and modified gingival index score showed a statistically significant difference (P = 0.005 and 0.007, respectively) in group I and II. There was a definite reduction in the ORG 1, ORG 2, scores and BANA test score in both groups I and II.

CONCLUSIONS:Oil pulling therapy has been equally effective like chlorhexidine on halitosis and organisms, associated with halitosis.

BACKGROUND:The current study was performed to determine the effects of cumin cyminum L. intake on weight loss and metabolic profiles among overweight subjects.

METHODS:This randomized double-blind placebo-controlled clinical trial was conducted among 78 overweight subjects (male, n = 18; female, n = 60) aged 18-60 years old. Participants were randomly assigned into three groups to receive: (1) cumin cyminum L. capsule (n = 26); (2) orlistat120 capsule (n = 26) and (3) placebo (n = 26) three times a day for 8 weeks. Anthropometric measures and fasting blood samples were taken at baseline and after 8 weeks of intervention.

RESULTS:Consumption of the Cuminum cyminum L. and orlistat120 resulted in a similar significant decrease in weight (-1.1± 1.2 and -0.9 ± 1.5 vs. 0.2 ± 1.5 kg, respectively, p = 0.002) and BMI (-0.4 ± 0.5 and -0.4 ± 0.6 vs. 0.1 ± 0.6 kg/m(2), respectively, p = 0.003) compared with placebo. In addition, taking Cuminum cyminum L., compared with orlistat and placebo, led to a significant reduction in serum insulinlevels (-1.4 ± 4.5 vs. 1.3 ± 3.3 and 0.3 ± 2.2 µIU/ml, respectively, p = 0.02), HOMA-B (-5.4 ± 18.9 vs. 5.8 ± 13.3 and 1.0 ± 11.0, respectively, p = 0.02) and a significant rise in QUICKI (0.01 ± 0.01 vs. -0.005 ± 0.01 and -0.004 ± 0.01, respectively, p = 0.02).

CONCLUSION:Taking cumin cyminum L. for eight weeks among overweight subjects had the same effects of orlistat120 on weight and BMI and beneficial effects on insulin metabolism compared with orlistat120 and placebo.© 2015 S. Karger AG, Basel.

OBJECTIVE: This study was undertaken to answer the question: "Is Arnica D4 as efficacious as diclofenac in relation to symptoms and wound healing after foot surgery?" METHODS: In this randomized double-blinded, parallel-group study (GCP-standard), the efficacy of Arnica D4 10 pillules (taken orally, 3 times per day) and diclofenac sodium, 50 mg (taken orally, 3 times per day) were investigated for equivalence in 88 patients 4 days after hallux valgus surgery. Outcome parameters were (1) postoperative irritation, (2) patient mobility, (3) rated pain, and (4) use of analgesics. The hierarchic equivalence test based on one-sided Wilcoxon-Mann-Whitney-U confidence intervals (CIs) was used. Equivalence was perceived, when the lower margin of the 95% CI was>0.36 corresponding to a range of equivalence of 1/2 standard deviation. RESULTS: Arnica D4 and diclofenac were equivalent for wound irritation (lower margin of the 95% CI on day 4: 0.4729 for rubor; 0.3674 for swelling; 0.4106 for calor) and patient mobility (0.4726). A descriptive analysis showed the superiority of Arnica D4 with respect to patient mobility (p = 0.045). With respect to pain, Arnica D4 was inferior to diclofenac (lower margin of the 95% CI 0.026). No significant differences were found regarding the use of additional analgesics during the 4 postoperative days (Dipidolor, Janssen-Cilag, Neuss, Germany; p = 0.54; Tramal, Grünenthal, Aachen, Germany; p = 0.1; and Novalgin, AVENTIS-Pharma, Bad Soden, Germany; p = 0.1). Arnica D4 was significantly better tolerated than diclofenac (p = 0.049). Nine (9) patients (20.45%) of the diclofenac group and 2 (4.5%) of the Arnica D4 group reported intolerance. There was no disturbance in wound healing in any of the patients. Arnica D4 is 60% cheaper than diclofenac. CONCLUSIONS: After foot operations, Arnica D4 can be used instead of diclofenac to reduce wound irritation.

OBJECTIVE: To observe the therapeutic effect of suspended moxibustion at Baihui (GV 20) for insomnia. METHODS: 75 cases were divided randomly into two groups, with 40 cases in the treatment group treated by suspended moxibustion over Baihui (GV 20) and 35 cases in the control group treated by oral administration of Estazolam. RESULTS: The difference in therapeutic effect between the two groups was not statistically significant (P > 0.1). CONCLUSION: It was concluded that suspended moxibustion at Baihui (GV 20) is as effective as Estazolam for insomnia.

OBJECTIVE: To compare the efficacy and safety of a homeopathic remedy (Vertigoheel, Heel Inc, Albuquerque, NM) vs betahistine hydrochloride (active control) in the treatment of patients with vertigo of various origins in a confirmative equivalence trial. DESIGN: Randomized (1:1) double-blind controlled clinical trial. SETTING: Fifteen study centers (general practice) in Germany between November 1995 and November 1996. SUBJECTS: A total of 119 patients with vertigo of various origins (from whom 105 patients could be analyzed as intended per protocol). MAIN OUTCOME MEASURES: Frequency, duration, and intensity of vertigo attacks. RESULTS: Both homeopathic and conventional treatments showed a clinically relevant reduction in the mean frequency, duration, and intensity of the vertigo attacks. The therapeutic equivalence of the homeopathic remedy and betahistine was established statistically. CONCLUSIONS: Concerning the main efficacy variable, therapeutic equivalence between the homeopathic remedy and betahistine could be shown with statistical significance (confirmative analysis). Both remedies reduced the frequency, duration, and intensity of vertigo attacks during a 6-week treatment period. Also, vertigo-specific complaints were significantly reduced in both treatment groups.

Mushrooms are a source of dietary fiber (DF) with a cholesterol-lowering effect. However, their underlying mechanisms are poorly understood. The effect of DF-enriched fractions from three mushrooms species on cholesterol-related expression was studied in vitro. The Pleurotus ostreatus DF fraction (PDF) was used in mice models to assess its potential palliative or preventive effect against hypercholesterolemia. PDF induced a transcriptional response in Caco-2 cells, suggesting a possible cholesterol-lowering effect. In the palliative setting, PDF reduced hepatic triglyceride likely because Dgat1 was downregulated. However, cholesterol-related biochemical data showed no changes and no relation with the observed transcriptional modulation. In the preventive setting, PDF modulated cholesterol-related genes expression in a manner similar to that of simvastatin and ezetimibe in the liver, although no changes in plasma and liver biochemical data were induced. Therefore, PDF may be useful reducing hepatic triglyceride accumulation. Because it induced a molecular response similar to hypocholesterolemic drugs in liver, further dose-dependent studies should be carried out.

AIM:We tested the hypothesis that administrations of methanolic extracts of Musa sapientum sucker (MEMS) with exercises attenuated hyperglycemia in alloxan-diabetic rats.

MATERIALS AND METHODS:A total of 40 adult male rats were divided into equal eight groups. Normoglycemic Group A was Control. Alloxan (180 mg/kg, i.p.) was administered to rats in Groups B - H to induce diabetes. Group B (diabetic control) received physiological saline. Groups C - H received MEMS (5 mg/kg), MEMS (10 mg/kg), Glibenclamide (5 mg/kg), MEMS (5 mg/kg) + exercises, MEMS (10 mg/kg) + exercises and Exercises only, respectively. Changes in body weight, blood glucose levels (BGL) and pancreatic histology were evaluated during or at the end of experiment. Body weights and BGL of rats were expressed as mean± standard deviation and analyzed using the statistical software program SPSS 15. Statistical comparisons were done using the Student's t-test for unpaired samples. Differences between groups were determined as significant at P ≤ 0.05.

RESULTS:Significantly (P<0.05) decreased bodyweight was observed in B and H compared to A and C - G. Treatment with MEMS significantly (P<0.05) decreased elevated BGL in C and D. Hypoglycemic effect of MEMS appeared enhanced with exercises in F and G. Exercises regimen alone (H) resulted in percentage reduction in BGL lower than those of C - G. Histopathological examinations revealed normal pancreas (A), atrophied islet cells (B), hyperplasia with adequate population of islet cells (C - G), and reduced hyperplasia of islet cells (H).

CONCLUSION:MEMS with exercises attenuated hyperglycemia in alloxan-diabetic rats.

WHAT IS KNOWN AND OBJECTIVE:Antiepileptic drugs often produce serious adverse effects, and many patients do not respond to them properly. Phytocannabinoids produce anticonvulsant effects in preclinical and preliminary human studies, and appear to produce fewer adverse effects than available antiepileptic drugs. The present review summarizes studies on the anticonvulsant properties of phytocannabinoids.

METHODS:Literature search using the PubMed database to identify studies on phytocannabinoids and epilepsy.

RESULTS AND DISCUSSION:Preclinical studies suggest that phytocannabinoids, especially cannabidiol and cannabidivarin, have potent anticonvulsant effects which are mediated by the endocannabinoid system. Human studies are limited in number and quality, but suggest that cannabidiol has anticonvulsant effects in adult and infantile epilepsy and is well tolerated after prolonged administration.

WHAT IS NEW AND CONCLUSION:Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects. Cannabidiol and cannabidivarin should be tested in randomized, controlled clinical trials, especially in infantile epileptic syndromes.

In this study, combinations of Ginkgo biloba leaf extract (EGb761) plus the carotenoid antioxidant astaxanthin (ASX) and vitamin C were evaluated for a summative dose effect in the inhibition of asthma-associated inflammation in asthmatic guinea-pigs. Ovalbumin-sensitized Hartley guinea-pigs challenged with ovalbumin aerosol to induce asthma, were administered EGb761, ASX, vitamin C or ibuprofen. Following killing, bronchoalveolar lavage (BAL) fluid was evaluated for inflammatory cell infiltrates and lung tissue cyclic nucleotide content. Each parameter measured was significantly altered to a greater degree by drug combinations, than by each component acting independently. An optimal combination was identified that included astaxanthin (10 mg/kg), vitamin C (200 mg/kg) and EGb761 (10 mg/kg), resulting in counts of eosinophils and neutrophils each 1.6-fold lower; macrophages 1.8-fold lower, cAMP 1.4-fold higher; and cGMP 2.04-fold higher than levels in untreated, asthmatic animals (p<0.05). In conclusion, EGb761, ASX and vitamin C are shown here to interact summatively to suppress inflammation with efficacy equal to or better than ibuprofen, a widely used non-steroidal antiinflammatory drug (NSAID). Such combinations of non-toxic phytochemicals constitute powerful tools for the prevention of onset of acute and chronic inflammatory disease if consumed regularly by healthy individuals; and may also augment the effectiveness of therapy for those with established illness.

The use of complementary and alternative medicine (CAM) has increased in the United States and more patients are seeking CAM therapies for control of pain. The present investigation tested the efficacy of orally administered anthocyanins extracted from tart cherries on inflammation-induced pain behavior in rats. Paw withdrawal latency to radiant heat and paw withdrawal threshold to von Frey probes were measured. The first set of experiments examined the effects of tart cherry anthocyanins (400 mg/kg) on the nociceptive behaviors and edema associated with inflammation induced by intraplantar injection of 1% carrageenan. These studies also included tests of motor coordination. The second set of experiments determined if tart cherry anthocyanins (15, 85, and 400 mg/kg) dose-dependently affected the inflammation induced by intraplantar injection of 25% complete Freund's adjuvant. We found that tart cherry extracts reduce inflammation-induced thermal hyperalgesia, mechanical hyperalgesia and paw edema. The suppression of thermal hyperalgesia was dose-dependent and the efficacy of highest dose (400 mg/kg) was similar to indomethacin (5 mg/kg). The highest dose anthocyanin (400 mg/kg) had no effects on motor function. These data suggest that tart cherry anthocyanins may have a beneficial role in the treatment of inflammatory pain. The antihyperalgesic effects may be related to the anti-inflammatory and antioxidant properties of anthocyanins. A better understanding of the modulatory role of dietary constituents and phytonutrients on pain will offer further therapeutic options for treating patients with persistent and chronic pain conditions.

OBJECTIVES: The purpose of this study was to examine whether the natural herb clove can replace benzocaine as a topical anesthetic. METHODS: Topical agents were applied to the maxillary canine buccal mucosa of 73 adult volunteers. Four substances were tested in the study: (1) homemade clove gel, (2) benzocaine 20% gel, (3) placebo that resembles clove and (4) a placebo that resembled benzocaine. After 5 min of material application in a randomized, subject-blinded manner, each participant received two needle sticks. Pain response was registered using a 100 mm visual analogue pain scale. RESULTS: Both clove and benzocaine gels had significantly lower mean pain scores than placebos (p=0.005). No significant difference was observed between clove and benzocaine regarding pain scores. CONCLUSION: Clove gel might possess a potential to replace benzocaine as a topical agent before needle insertion.