Moraxella bovis is considered as the primary etiologic agent of IBK. Clinical signs associated with this contagious disease progressively include epiphora, blepharospasm, miosis, edema, corneal ulceration, descemetocele, and blindness.1 Economic losses attributable to IBK include reduced weight gains, treatment costs, and ocular disfigurement.1 In 1997, the USDA National Animal Health Monitoring System2 for beef cattle estimated that IBK was the most prevalent disease among breeding females and was the second most prevalent disease among calves > 3 weeks old. Environmental factors that augment the clinical effects of M bovis include UV light, wind, dust, pollens, ammonia, and face flies (Musca autumnalis).3
In some herds, 100% of all yearling calves may be affected by M bovis each year. The tendency of cases of IBK to be distributed over the entire summer combined with the lack of effective immunoprophylaxis increases the need for antimicrobials that can be used to effectively treat calves with minimum handling and expense. Treatment alternatives for IBK include subconjunctival and topical administration of penicillin4; IM administration of tetracycline5 and florfenicol6,7; and administration of tilmicosin, a macrolide, by various routes.8 Although subconjunctival administration of penicillin is considered as a common treatment for cattle with IBK, results of a controlled trial did not indicate efficacy.4 Additional chemotherapeutic agents would be useful because of the potential for antimicrobial resistance and the need for repetitive applications of some drugs. Repetitive treatments increase costs and enhance the risk of iatrogenic transmission of M bovis.
Tulathromycin is a semisynthetic macrolide that is chemically related to azithromycin. Tulathromycin is a member of the triamilide subclass of macrolide antimicrobials and is approved for use for treatment of cattle with bacterial pneumonia. Following a single SC administration (2.5 mg/kg [1.1 mg/lb]), tulathromycin reaches a peak plasma concentration of 414 ng/mL by 0.25 hours.9 The plasma half-life of tulathromycin is 92 hours.9 The drug is excreted through urine and feces in approximately equal amounts with apparent bioavailability of 91% after a single SC injection.9 At steady state, the drug has a volume of distribution of 11 L/kg.9 Although antimicrobial persistence in ocular tissue has not been studied, tulathromycin reaches lung concentrations as much as 325 times that of serum and persists at therapeutic concentrations for pulmonary pathogens for as long as 10 days. Results of a preliminary study using serial antimicrobial dilution assays indicated that the Tifton 1 strain of M bovis was susceptible to concentrations of tulathromycin > 0.5 mg/mL, which constitutes an achievable plasma concentration in parenterally treated calves. The long halflife and high bioavailability of tulathromycin, and the in vitro efficacy against M bovis, suggest that the drug may be a cost-effective treatment for IBK. The purpose of the study reported here was to determine whether a single injection of tulathromycin was effective in reducing healing times of corneal ulcers induced by M bovis in cattle.
Materials and Methods
Cattle—Thirty castrated male Holstein calves ranging in age from 5 to 6 months old were purchased from a dairy. Calves had not been treated with antimicrobials and had not been vaccinated for M bovis. To determine whether calves were free of M bovis, ocular secretions were collected from each eye of each calf for 3 consecutive days prior to inoculation. Secretions were streaked onto 5% bovine blood agar plates, which were incubated for 24 hours before plates were examined for M bovis growth. Prior to the study, eyes of all calves were illuminated and examined. Calves were chosen for the study if their eyes were free of visible lesions and results of 3 serial microbial cultures of ocular secretions for M bovis were negative. Calves were handled in accordance with approved animal care and use protocols.
Housing—Calves were housed in groups of 2 or 4 animals/stall. Stalls were enclosed in a mechanically ventilated, fly-proof building. Calves had free access to pelleted alfalfa hay and water, and concentrate was fed at a rate of 1 kg/head/d (2.2 lb/head/d) until study day 14, when 1 calf died suddenly of bloat. At that time, long-stemmed oat hay was made freely available to all calves, and feeding of concentrate was discontinued. To reduce the iatrogenic spread of M bovis, personnel examining calves wore disposable obstetric sleeves, rubber examination gloves, and nondisposable plastic aprons. The plastic aprons were washed in water containing 1% chlorhexidine after each calf was examined.
Experimental design—Calves were infected with M bovis for 3 consecutive days designated as day −3, −2, and −1, respectively. Beginning on day 0 (24 hours after the final inoculation), both eyes of calves were examined and assigned clinical scores. Following that examination, calves were weighed and randomly allocated to group 1 (treated calves) or group 2 (control calves) by use of a stratified block design that randomized simultaneously for both body weight and severity of ocular lesions. For randomization, calves were ranked in order of decreasing ocular lesion score and increasing body weight within ocular lesion score. For calves with bilateral corneal ulcers, the eye with the highest ocular lesion score was used for randomization. By use of this method, 15 blocks of 2 calves each were allocated. Each isolation pen housed 1 to 2 blocks of calves.
On day 0, calves in group 1 were treated with tulathromycin (2.5 mg/kg, SC); calves in group 2 received an equivalent volume of saline (0.9% NaCl) solution administered SC. All injections were given over the lateral cervical muscles. Personnel administering treatments did not participate in the clinical evaluation of eyes, and evaluators were unaware of the treatment status of calves.
Experimental infection—Both eyes of each calf were irradiated with a sunlampa at a distance of 60 cm for 10 minutes and then were inoculated by instilling 1 X 1010 colonyforming units of β-hemolytic M bovis (Tifton 1 strain) in 1 mL of trypticase soy broth dropwise onto the corneal surface until it was absorbed by the nasolacrimal system. Irradiation and experimental infection with M bovis were performed on days −3, −2, and −1. Inoculant bacteria, the Tifton 1 strain of M bovis, were propagated and harvested as previously described.5
Ocular examinations—After the last M bovis inoculation (day −1), calves were treated on day 0, and both eyes of each calf were examined daily for 21 days. For examination, fluorescein dye was instilled into each eye. After several minutes, eyes were irrigated with sterile saline solution to remove excess fluorescein dye. Eyes were illuminated with a high-intensity incandescent lamp. Corneal lesions were graded by assigning clinical scores according to the following criteria: 1, no visible lesions; 2, conjunctivitis without corneal ulceration; 3, corneal ulcer < 5 mm in diameter; 4, corneal ulcer ≥ 5 mm in diameter; 5, corneal perforation; and 6, loss of aqueous humor.
Both eyes of all calves were photographed daily by use of a 35-mm color slide film camera with the lens fixed to achieve a constant 3-fold image reduction. A ruled marker was included in the photograph for additional calibration. For surface area measurement, the magnified photographic images were projected onto bond paper, and the corneal ulcers, as defined by the area of fluorescein stain uptake, were traced. Surface areas of the tracings were measured by use of imaging software.b
Ocular secretions were collected from the conjunctival sacs of each eye. Secretions were collected daily from days 0 through 6 and then again on days 9, 12, 15, 18, and 21. For collection of ocular secretions, sterile polyester–tippedcswabs were rubbed in the inferior conjunctival sac. Swab specimens were immediately streaked onto 5% bovine blood agar plates for bacterial isolation and were incubated for 24 hours before being examined for M bovis growth. Colonies with b hemolysis and resembling M bovis were subcultured until pure and were positively identified by use of Gram stain morphology and biochemical criteria that were characteristic for the M bovis Tifton 1 isolate. These criteria included peptonization of litmus milk, gelatin hydrolysis, no reaction in O-F medium, inability to reduce nitrates to nitrogen, oxidase production, and lack of growth on MacConkey agar plates.
Statistical analysis—Cure rates were determined for each day of the study by comparing the ocular lesion scores among groups by use of the Cochran-Mantel-Haenszel statistic. Although ulcer surface area measurements were recorded for both eyes of each calf, only eyes that had at least 1 ulcer measurement that was not zero were included in the analysis of ulcer surface measurements; therefore, eyes that were considered normal throughout the study were not included in the analysis. Treatment differences for corneal ulcer surface area measurements were analyzed by use of a repeated-measures linear mixed model that included terms for the fixed effects of treatment, day of study, and interaction along with the random effects of block, block by treatment, eye within the calf, and block by treatment by day of study interaction. Ulcer scores on day 0 were used as a possible covariant, and the necessary covariant terms were added to the model where appropriate. Appropriate contrasts between treatments on day of study were made within the mixed effects model of a software programd after requiring a significant treatment or treatment by day of study effect. Improvement in ocular lesion scores was determined in each group by use of the Kruskal-Wallis test. The frequency of M bovis isolation was analyzed by use of the Fisher exact test. Survival analysis of surface area measurements was performed by use of softwaree; the Tarone-Ware statistic was used to test for differences among groups. For all analyses, values of P < 0.05 were considered significant.
Results
One calf in group 2 died suddenly from bloat on day 14. Data from this calf were included in the statistical evaluations from day 0 until the day prior to death. On day 0, 14 calves had developed corneal ulcers in 1 eye, and 16 calves had developed ulcers in both eyes. After random allocation, the distribution of calves with unilateral and bilateral ulcers was as follows: 8 and 7 in group 1 and 9 and 6 in group 2. Of the 9 calves with unilateral ulcers in group 2, 6 became affected in both eyes during the 21-day observation period. None of the calves in group 1 that had initial unilateral infections developed ulcers bilaterally during the observation period.
Moraxella bovis was isolated from significantly (P < 0.001) fewer treated calves (20% with positive results) than from control calves (65% with positive results; Table 1). Moraxella bovis was not isolated from ocular secretions of treated calves at 24 hours (day 1) and was isolated from 1 calf on day 2 and a different calf on day 3. Moraxella bovis was not isolated from any of the treated calves on days 4 through 6 (beginning on day 6, microbial cultures of the cornea were obtained every 3 days; therefore, no microbial cultures were obtained on day 7 or 8). On days 15, 18, and 21, M bovis was isolated from eyes of 7, 6, and 5 treated calves, respectively. On those days, M bovis was isolated from ocular secretions of 10, 11, and 11 of 14 control calves, respectively.
Number of calves experimentally infected with Moraxella bovis on 3 consecutive days from which M bovis was isolated from ocular secretions 24 hours after the final inoculation (day 0) and on various days after administration of a single treatment with tulathromycin (2.5 mg/kg [1.1 mg/lb], SC; n = 15) or saline (0.9% NaCl) solution, SC (control; 15).
| Group | Days after treatment | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 | 6 | 9 | 12 | 15 | 18 | 21 | |
| Control | 14 | 12 | 4 | 9 | 9 | 7 | 10 | 10 | 11 | 10a | 11a | 11a |
| Tulathromycin | 14 | 0* | 1 | 1* | 0* | 0* | 0* | 3* | 1* | 7 | 6* | 5* |
Significantly (P < 0.05) different from control group.
One calf in the control group died on day 14; therefore, only 14 calves were examined on days 15, 18, and 21.
The cumulative survival functions for ulcer healing time for both groups of calves, with ocular lesion score as the parameter of interest, are depicted (Figure 1). The Kaplan-Meier estimate of median time to cure was 9.1 days for treated calves. Because ulcer resolution did not attain 50% in control calves during the observation period, the estimate of mean time to cure may not be accurate. However, at 9.1 days, 1 control calf had spontaneous resolution of a corneal ulcer. The survival curves were significantly (P < 0.01) different between the 2 groups. The odds (Mantel-Haenszel) of having a corneal ulcer at the end of the trial (day 21) were 31fold greater in control calves than in treated calves.
Cumulative proportion of calves with corneal ulcers after experimental infection with Moraxella bovis and administration of a single treatment with tulathromycin (2.5 mg/kg [1.1 mg/lb], SC; n = 15) or saline (0.9% NaCl) solution (control; 15). The median healing time was significantly (P < 0.01) less in calves treated with tulathromycin than in control calves.
Citation: Journal of the American Veterinary Medical Association 229, 4; 10.2460/javma.229.4.557
Cumulative proportion of calves with corneal ulcers after experimental infection with Moraxella bovis and administration of a single treatment with tulathromycin (2.5 mg/kg [1.1 mg/lb], SC; n = 15) or saline (0.9% NaCl) solution (control; 15). The median healing time was significantly (P < 0.01) less in calves treated with tulathromycin than in control calves.
Citation: Journal of the American Veterinary Medical Association 229, 4; 10.2460/javma.229.4.557
Cumulative proportion of calves with corneal ulcers after experimental infection with Moraxella bovis and administration of a single treatment with tulathromycin (2.5 mg/kg [1.1 mg/lb], SC; n = 15) or saline (0.9% NaCl) solution (control; 15). The median healing time was significantly (P < 0.01) less in calves treated with tulathromycin than in control calves.
Citation: Journal of the American Veterinary Medical Association 229, 4; 10.2460/javma.229.4.557
Ocular lesion scores in calves in both groups were not significantly different on day 0 (Table 2). By day 10, treated calves had significantly (P < 0.05) lower ocular lesion scores than control calves. From day 3 through day 18, the least squares means for corneal ulcer surface area measurements for each observation day in treated calves were significantly (P < 0.05) lower than that in control calves (Table 3).
Frequency (percentage) of ocular lesion scores for calf eyes within each treatment group (n = 30)a,b beginning 24 hours after the third and final inoculation of M bovis and assessed on day 0 just prior to receiving tulathromycin (2.5 mg/kg, SC) or saline solution, SC (control), then daily for 21 days.
| Day of study | Treatment group | Ocular lesion score* | |||||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | ||
| 0 | Control | 6 (20) | 3 (10) | 12 (40) | 9 (30) | 0 (0) | 0 (0) |
| Tulathromycin | 5 (16.7) | 3 (10) | 15 (50) | 7 (23.3) | 0 (0) | 0 (0) | |
| 1 | Control | 4 (13.3) | 3 (10) | 12 (40) | 11 (36.7) | 0 (0) | 0 (0) |
| Tulathromycin | 6 (20) | 2 (6.7) | 11 (36.7) | 11 (36.7) | 0 (0) | 0 (0) | |
| 2 | Control | 6 (20) | 1 (3.3) | 9 (30) | 14 (46.7) | 0 (0) | 0 (0) |
| Tulathromycin | 7 (23.3) | 4 (13.3) | 6 (20) | 13 (43.3) | 0 (0) | 0 (0) | |
| 3 | Control | 7 (23.3) | 2 (6.7) | 9 (30) | 12 (40) | 0 (0) | 0 (0) |
| Tulathromycin | 8 (26.7) | 5 (16.7) | 7 (23.3) | 10 (33.3) | 0 (0) | 0 (0) | |
| 4 | Control | 7 (23.3) | 6 (20) | 6 (20) | 11 (36.7) | 0 (0) | 0 (0) |
| Tulathromycin | 8 (26.7) | 5 (16.7) | 9 (30) | 8 (26.7) | 0 (0) | 0 (0) | |
| 5 | Control | 4 (13.3) | 9 (30) | 6 (20) | 11 (36.7) | 0 (0) | 0 (0) |
| Tulathromycin | 8 (26.7) | 6 (20) | 9 (30) | 7 (23.3) | 0 (0) | 0 (0) | |
| 6 | Control | 4 (13.3) | 9 (30) | 6 (20) | 11 (36.7) | 0 (0) | 0 (0) |
| Tulathromycin | 8 (26.7) | 11 (36.7) | 5 (16.7) | 6 (20) | 0 (0) | 0 (0) | |
| 7 | Control | 6 (20) | 7 (23.3) | 5 (16.7) | 12 (40) | 0 (0) | 0 (0) |
| Tulathromycin | 8 (26.7) | 12 (40) | 8 (26.7) | 2 (6.7) | 0 (0) | 0 (0) | |
| 8 | Control | 5 (16.7) | 7 (23.3) | 5 (16.7) | 13 (43.3) | 0 (0) | 0 (0) |
| Tulathromycin | 8 (26.7) | 12 (40) | 7 (23.3) | 3 (10) | 0 (0) | 0 (0) | |
| 9 | Control | 5 (16.7) | 8 (26.7) | 4 (13.3) | 13 (43.3) | 0 (0) | 0 (0) |
| Tulathromycin | 8 (26.7) | 15 (50) | 4 (13.3) | 3 (10) | 0 (0) | 0 (0) | |
| 10 | Control | 6 (20) | 7 (23.3) | 4 (13.3) | 13 (43.3) | 0 (0) | 0 (0) |
| Tulathromycin | 7 (23.3) | 16 (53.3) | 4 (13.3) | 3 (10) | 0 (0) | 0 (0) | |
| 11 | Control | ± (20) | 6 (20) | 7 (23.3) | 10 (33.3) | 1 (3.3) | 0 (0) |
| Tulathromycin | 8 (26.7) | 18 (60) | 1 (3.3) | 3 (10) | 0 (0) | 0 (0) | |
| 12 | Control | 4 (13.3) | 9 (30) | 4 (13.3) | 12 (40) | 1 (3.3) | 0 (0) |
| Tulathromycin | 8 (26.7) | 19 (63.3) | 0 (0) | 3 (10) | 0 (0) | 0 (0) | |
| 13 | Control | 4 (13.3) | 10 (33.3) | 4 (13.3) | 11 (36.7) | 1 (3.3) | 0 (0) |
| Tulathromycin | 8 (26.7) | 19 (63.3) | 1 (3.3) | 2 (6.7) | 0 (0) | 0 (0) | |
| 14 | Control | 4 (14.3) | 9 (32.1) | 5 (17.9) | 9 (32.1) | 1 (3.6) | 0 (0) |
| Tulathromycin | 8 (26.7) | 19 (63.3) | 2 (6.7) | 1 (3.3) | 0 (0) | 0 (0) | |
| 15 | Control | 3 (10.7) | 9 (32.1) | 5 (17.9) | 10 (35.7) | 1 (3.6) | 0 (0) |
| Tulathromycin | 12 (40) | 15 (50) | 3 (10) | 0 (0) | 0 (0) | 0 (0) | |
| 16 | Control | 4 (14.3) | 8 (28.6) | 6 (21.4) | 9 (32.1) | 1 (3.6) | 0 (0) |
| Tulathromycin | 16 (53.3) | 12 (40) | 2 (6.7) | 0 (0) | 0 (0) | 0 (0) | |
| 17 | Control | 3 (10.7) | 8 (28.6) | 9 (32.1) | 8 (28.6) | 0 (0) | 0 (0) |
| Tulathromycin | 18 (60) | 12 (40) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| 18 | Control | 3 (10.7) | 8 (28.6) | 9 (32.1) | 8 (28.6) | 0 (0) | 0 (0) |
| Tulathromycin | 15 (50) | 15 (50) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| 19 | Control | 3 (10.7) | 11 (39.3) | 7 (25) | 7 (25) | 0 (0) | 0 (0) |
| Tulathromycin | 19 (63.3) | 10 (33.3) | 1 (3.3) | 0 (0) | 0 (0) | 0 (0) | |
| 20 | Control | ± (21.4) | 11 (39.3) | 6 (21.4) | 5 (17.9) | 0 (0) | 0 (0) |
| Tulathromycin | 25 (83.3) | 5 (16.7) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
| 21 | Control | 9 (32.1) | 10 (35.7) | 5 (17.9) | 4 (14.3) | 0 (0) | 0 (0) |
| Tulathromycin | 26 (86.1) | 4 (13.3) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |
Ocular lesion scores: 1, normal eye (no uptake of fluorescein dye); 2, conjunctivitis without corneal ulceration (no uptake of fluorescein dye); 3, corneal ulcer < 5 mm in diameter; 4, corneal ulcer ≥ 5 mm in diameter; 5, corneal perforation; 6, loss of vitreous humor.
For the control group, n = 30 eyes from day 0 through day 13. From day 14 through day 21, n = 28 eyes because 1 calf died on day 14.
For the tulathromycin group, n = 30 eyes from day 0 through day 21.
Least squares means ± SD of corneal ulcer surface area measurements (mm2) in calves experimentally infected with M bovis after administration of a single treatment with tulathromycin (2.5 mg/kg, SC; n = 15) or saline solution (control; 15).
| Day of study | Control | Tulathromycin | P value |
|---|---|---|---|
| 1 | 21.6 ± 5.25 | 21.1 ± 1.64 | 0.927 |
| 2 | 22.2 ± 5.08 | 16.5 ± 1.59 | 0.290 |
| 3 | 24.4 ± 5.08 | 11.8 ± 1.59 | 0.018 |
| 4 | 25.9 ± 5.08 | 9.6 ± 1.59 | 0.002 |
| 5 | 26.3 ± 5.08 | 7.4 ± 1.59 | < 0.001 |
| 6 | 22.9 ± 5.08 | 5.5 ± 1.62 | 0.001 |
| 7 | 23.6 ± 5.08 | 5.2 ± 1.59 | 0.001 |
| 8 | 23.9 ± 5.13 | 4.4 ± 1.59 | < 0.001 |
| 9 | 25.5 ± 5.08 | 3.7 ± 1.59 | < 0.001 |
| 10 | 24.8 ± 5.08 | 2.8 ± 1.59 | < 0.001 |
| 11 | 25.0 ± 5.08 | 2.2 ± 1.59 | < 0.001 |
| 12 | 24.8 ± 5.08 | 1.6 ± 1.59 | < 0.001 |
| 13 | 22.0 ± 5.08 | 1.2 ± 1.59 | < 0.001 |
| 14 | 17.4 ± 5.19 | 1.2 ± 1.59 | 0.003 |
| 15 | 17.1 ± 5.19 | 0.6 ± 1.59 | 0.003 |
| 16 | 13.3 ± 5.19 | 0.6 ± 1.59 | 0.019 |
| 17 | 12.1 ± 5.25 | 0.2 ± 1.59 | 0.030 |
| 18 | 11.1 ± 5.25 | 0.2 ± 1.59 | 0.046 |
| 19 | 9.6 ± 5.19 | 0.2 ± 1.59 | 0.084 |
| 20 | 7.3 ± 5.19 | 0.2 ± 1.59 | 0.193 |
| 21 | 5.5 ± 5.19 | 0.2 ± 1.59 | 0.325 |
Discussion
In the study reported here, tulathromycin was effective for the treatment of corneal ulcers in calves experimentally infected with M bovis. Beneficial effects of treatment included shorter healing times, lower ocular lesion scores, reduced size of corneal ulcers, and development of fewer ulcers bilaterally, compared with control calves. The low frequency of M bovis isolation from treated calves on days 1 through 12 indicated that tulathromycin distributed into ocular tissues and lacrimal secretions at inhibitory concentrations. The reisolation of M bovis on days 9 through 21 could have indicated either incomplete cure and bacterial regrowth or reinoculation of M bovis from control calves that were cohabitating with treated calves. Calves were housed to control environmental variables that affect this disease. Because adequate housing for isolation of individual calves was not available, calves were randomly allocated so that equal numbers of control and treated calves shared stall space. This housing arrangement had the unfortunate potential to allow cross contamination of treated calves by untreated control calves. Because corneal ulcers were experimentally induced and calves were housed indoors in a screened barn, calves were not exposed to additional risk factors such as sunlight, plant pollens, face flies, and dust, and the efficacy of tulathromycin for treatment of naturally occurring IBK is not known. In addition, the comparative efficacy of tulathromycin with antimicrobials that are commonly used for treating naturally occurring IBK is not known.
In our study, response variables included ocular lesion scores and surface area measurements. Surface area measurement was a continuous variable with objective properties that was more consistent between observers than ocular lesion scores. Neither measure accounted for the depth of the individual ulcer; however, the consistent thickness of the cornea in cattle, in conjunction with results of a previous study5 indicating an exponential association between sequential surface area measurements, suggests that changes of surface area measurements were related to clinical responses in treated calves. Clinical measures of blepharospasm, photophobia, and ocular discharge often indicated a rapidly healing ulcer irrespective of score, surface area, or depth of a corneal ulcer. Calves were treated after the eyes had been exposed to UV light and to hemolytic M bovis for 3 days. The duration between experimental infection and treatment was chosen to maximize the number of calves that developed ulcers while simultaneously reducing the chances for existing ulcers to develop into a longstanding lesion.
ABBREVIATIONS
| IBK | Infectious bovine keratoconjunctivitis |
Sylvania GS60, Osram Sylvania, Danvers, Mass.
NIH image, National Institute of Health, Bethesda, Md.
Dacron, Dupont, Kingston, NC.
SAS (PROC MIXED), SAS Institute Inc, Cary, NC.
SPSS, version 11, SPSS Inc, Chicago, Ill.
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