[Botulinum toxin type A (Relatox) in transition from medication overuse to non-overuse status in patients with chronic migraine: a subgroup analysis of phase IIIb randomized single-blind multicenter active-controlled parallel-group trial]. / Botulinicheskii toksin tipa A (Relatoks) v preodolenii lekarstvennogo zloupotrebleniya u patsientov s khronicheskoi migren'yu: podgruppovoi analiz rezul'tatov mnogotsentrovogo prostogo slepogo randomizirovannogo sravnitel'nogo issledovaniya IIIb fazy.

OBJECTIVE: To access the effect of Relatox, the first Russian botulinum toxin type A, in patients with chronic migraine (CM) and medication overuse (MO). MATERIAL AND METHODS: In phase IIIb single-blind randomized multicenter active-controlled parallel-group study, patients with CM were randomized to once intramuscular injections of Relatox (n=101) or onabotulinumtoxin A injections - Botox (n=108). This subgroup analysis evaluated the percentage of patients who transition from medication overuse to non overuse status from baseline; mean changes in the number of headache days, migraine headache days, acute headache medication intakes days, headache intensity, proportion of patients who had a ≥50% reduction in headache days, proportion of the patients with severe (≥60) Headache Impact Test-6 score and with a severe (≥21) MIDAS score in a 28-day periods in each treatment among patients with baseline acute medication overuse via repeated measures. RESULTS: Of 209 patients with CM, 100% met medication overuse criteria. Relatox and Botox demonstrated significant improvement for overall least squares mean change in headache days, migraine headache days, headache intensity; and headache-related disability and quality of life in CM patients with baseline MO, without differences between the groups. 75% and 70% patients in the Relatox and Botox groups, respectively, achieved ≥50% reduction in headache days from baseline (OR 1.58, CI 95% 0.84; 3.02, p=0.155). Furthermore, Relatox and Botox significant reduced average medication overuse rates in patient with CM and MO at baseline. 62% of patients in the Relatox group and 48% of patients in the Botox group transitioned from medication overuse to non overuse status compared from baseline (OR 2.07, CI 95% 0.91; 4.62, p=0.044). Relatox group had greater reductions than the Botox group in the percentage of patients with acute migraine-specific medication (triptan) overuse (p=0.050). CONCLUSION: The results demonstrate highly prevalent of medication overuse among individuals with CM. This analysis provides evidence that the Russian botulinum toxin type A Relatox significantly improves measures of headache symptoms, quality of life and headache-related disability, and also significantly greater, compared to Botox, reduces migraine-specific medication consumption in patients with chronic migraine who overuse acute medications.

[Botulinum toxin type A (Relatox) in the treatment of chronic migraine in adults: results of phase IIIb, randomized, one-blind, multicenter, active-controlled, parallel-group trial]. / Botulinicheskii toksin tipa A (Relatoks) v lechenii khronicheskoi migreni u vzroslykh: rezul'taty mul'titsentrovogo prostogo slepogo randomizirovannogo sravnitel'nogo issledovaniya IIIb fazy.

OBJECTIVE: To access the efficacy and safety of the first Russian botulinum toxin type A (Relatox) as a headache prophylaxis in adult with chronic migraine (CM). MATERIAL AND METHODS: The randomized, one-blind, multicenter, active-controlled, parallel-group trial study involved 209 patients with CM aged from 19 to 65 years. The patients were randomized to injections of the Russian botulinum toxin type A - Relatox (n=101) or onabotulinumtoxinA injections - Botox (n=108). The duration of the study was 16 weeks, which included five visits of patients every 4 weeks. Relatox and Botox were injected once into seven muscle groups of the head and neck at a dose of 155-195 units. Primary efficacy variable was mean change from baseline in frequency of headache days after 12 weeks. Secondary efficacy variables were mean changes from the baseline to week 12 in frequency of migraine days, acute headache pain medication intakes days; headache intensity; proportion of patients achieving ≥50% reduction from baseline in headache days, the proportion of the patients with medication overuse, the proportion of the patients with severe (≥60) Headache Impact Test-6 score and with a severe (≥21) MIDAS score. RESULTS: Analyses demonstrated a large mean decrease from baseline in frequency of headache days, without statistically significant between-group differences Relatox vs Botox at week 12 (-10.89 vs -10.06; p=0.365) and at other time points. Significant differences from baseline were also observed for all secondary efficacy variables at all time points without differences between the groups. The proportion of patients achieving ≥50% reduction from baseline in headache days was 75.0% and 70% in the Relatox and Botox groups, respectively (OR, CI 95% 1.58 [0.84; 3.02], p=0.155). Adverse events (AE) occurred in 15.8% of Relatox patients and 15.7% of Botox patients (p=1.000). No unexpected AE were identified. CONCLUSION: The results demonstrate that the first Russian botulinum toxin type A (Relatox) is an effective prophylactic treatment for CM in adult patients. Relatox led to significant improvements from baseline in multiple measures of headache symptoms, headache-related disability and quality of life. For the first time, a comparative analysis of two botulinum toxin type A products in parallel groups showed no less (not inferior) efficacy and safety of Relatox relative to Botox in the treatment of CM in adults.

[Safety and efficacy of the Relatox in the treatment of patients with cervical dystonia (results of a multicenter simple blind comparative randomized study)]. / Bezopasnost' i effektivnost' preparata Relatoks v lechenii patsientov s tservikal'noi distoniei (rezul'taty mul'titsentrovogo prostogo slepogo sravnitel'nogo randomizirovannogo issledovaniya).

OBJECTIVE: The analysis of evaluation of the efficacy and safety of Relatox in patients with cervical dystonia (CD). MATERIAL AND METHODS: Russian multicenter simple comparative randomized clinical trial. The study involved 180 patients of both sexes aged 18-65 years from 3 research centers of the Russian Federation. All patients had previously established diagnosis of CD and were randomized to one of two groups at 1 visit after the inclusion procedure and signing of informed consent. Patients in group 1 (n=90) got injections of Relatox, in group 2 (n=90) - injections of Botox for the first time or no earlier than 4 months after the previous injection of Dysport 500 units, Botox 200 units or Xeomin 200 units. The assessment of changes in cervical dystonia followed, including of determination of changes in the severity of CD, assessed on the TWSTRS scale by the total score and by the defining values of the blocks, as well as on the scales: the Patient Global Impression of Improvement (PGI-I) and of adverse events (local and systemic reactions). Based on the form of cervical dystonia (torticollis, laterocollis, etc.), the drug was injected under electromyographic control into the target muscles: sternocleidomastoid, belt, trapezoidal, shoulder-lifting muscle. RESULTS: Equal efficacy, good tolerability and safety comparable to the comparison drug Botox was demonstrated in 12 weeks after injection of Relatox. The number of registered local and systemic reactions in both groups was insignificant and did not differ significantly (p>0.05). There were no significant differences in the results of laboratory parameters in patients of both groups (p>0.05). Serious adverse events were also not detected during the study. CONCLUSION: Obtained results indicate the safety, good tolerability and efficacy of Relatox in patients with CD comparable to Botox and can be recomemded for using by practitioners.

[Higher efficacy of botulinum toxin therapy for hemifacial spasm recurrence after vascular decompression. Case report and literature review]. / Uvelichenie effektivnosti botulinoterapii pri vozvrate simptomov gemifatsial'nogo spazma posle vaskulyarnoi dekompressii. Klinicheskii sluchai i obzor literatury.

Hemifacial spasm (HFS) is an involuntary synchronous tonic and/or clonic contraction of mimic muscles following ipsilateral facial nerve dysfunction. The last one is a result of neurovascular conflict between the facial nerve and vessel. Currently, vascular decompression is a pathogenetic treatment modality for primary HFS. Various authors describe postoperative recurrence of HFS, and botulinum toxin therapy remains the only option for these patients. We aimed to describe the efficacy of botulinum toxin therapy in patients with HFS recurrence after surgical vascular decompression. The article presents a female patient with a long-term history of HFS and botulinum toxin therapy (with different formulations). Efficacy of therapy gradually decreased (progressive reduction of intervals between injections). MRI revealed a close relationship between posterior inferior cerebellar artery and roots of acoustic-facial nerves near the brainstem. The patient underwent vascular decompression of the left facial nerve root under intraoperative monitoring with positive postoperative outcome. However, HFS symptoms recurred in 3 days after surgery. Botulinum toxin type A (BTA) injections were resumed with significant positive effect that can be explained by reduction of one of the factors involved into HFS. Thus, patients with HFS recurrence after vascular decompression may benefit from BTA therapy.

[The effectiveness of botulinum therapy of trigeminal neuralgia]. / Effektivnost' botulinoterapii pri trigeminal'noi nevralgii.

OBJECTIVE: To evaluate the treatment protocol with the use of onabotulinum toxin type A (botox) and the efficacy of a single botulinum therapy procedure for clinical manifestations in patients with trigeminal neuralgia (TN). MATERIAL AND METHODS: We studied 90 patients (57 women, 33 men), including 80 people with primary TN and 10 people with secondary TN. Then 20 patients with primary TN (11 women and 9 men, mean age 61.8 years) received local injections of onabotulinum toxin type A (botox). Clinical examination included taking anamnesis, assessment of pain on a visual analogue scale (VAS), assessment of the frequency of pain paroxysms, taking into account the average indicator (0 to 100 seizures during the day); neurosensory examination according to the developed protocol with the definition of pain, temperature, tactile sensitivity, the study of stimulus-dependent pain; MRI of the brain to diagnose neurovascular conflict. RESULTS: A month after the injections, the pain intensity practically did not change (8.5 versus 7.2 points on the VAS), but the number of paroxysms decreased (31.2 versus 22.5 seizures per day). Two months after the use of botox, the number of pain attacks continued to decrease (31.2 versus 17.7; Mann-Whitney U-test, p=0.006). At the same time, there was a decrease in pain intensity according to the VAS (8.5 versus 6.1, t-test 2.75 points; p=0.02). After three months, there was a decrease in the number of paroxysms from 31.2 to 9.2 (paired Student's test, p<0.001) and the severity of pain (8.85 versus 4.0 points on the VAS, paired t-test 3.95 points, p<0.001). There were significant differences in the average dose of carbamazepine (867.5 versus 670.8 after 3 months, t-test 196.7 mg, p=0.02). In TN patients who underwent destructive operations with exposure to the peripheral branches of the trigeminal nerve, signs of severe neurosensory deficit on the face and burning pain are added to the main symptoms, which corresponds to the clinical criteria of post-traumatic trigeminal neuropathy. CONCLUSION: Local injections of type A onabotulinum toxin (botox) are minimally invasive, safe and effective symptomatic therapy for patients with TN. Persistent sensory disturbances that develop in patients after destructive surgeries call into question the safety of these therapies for TN.

[Botulinum therapy of spastic forms of cerebral palsy in various locomotor patterns]. / Botulinoterapiya spasticheskikh form detskogo tserebral'nogo paralicha pri razlichnykh lokomotornykh patternakh.

Spasticity in patients with cerebral palsy (CP) is the main impediment to normal locomotion. The function of the Central Pattern Generator (CPG), i.e. a group of neural chains in the spinal cord, stands at the core of any rhythmical movement. CPG can generate locomotion patterns without supraspinal control, which can have both positive and negative impact on the ability to move. Performing the motor tasks such as walking, running and swimming, creates the consistent rhythmical movement of legs and arms through interaction between CPGs of upper and lower extremities. This interaction can cause the activation of pathological movement patterns in lower extremities in response to upper limb spasticity. Thus, neural chains in the spinal cord become the generator of pathologically increased excitation which has developed as a result of a focal lesion in the CNS. All the statements described above show the importance of introducing the upper limb injections of bFotulinum toxin A in the protocol in order to develop normal locomotion. The PUL study approved the optimal level of efficacy and favourable safety profile of botulinum toxin A in children with CP and upper limb muscle spasticity.

[The efficacy of botulinum therapy in treatment of delayed facial palsy after resection of vestibular schwannoma]. / Éffektivnost' botulinoterapii v lechenii otsrochennoi neiropatii litsevogo nerva posle udaleniia nevrinomy slukhovogo nerva.

Delayed facial palsy is a complication developing 3 or more days after surgery. The etiology and pathogenesis of this condition has not been fully explored, and there are no treatment standards for it. As in the case of Bell's paralysis, glucocorticosteroids (GCSs) are currently used to treat delayed facial palsy. However, patients with contraindications to GCSs need new therapy modalities. AIM: We aimed to evaluate the efficacy and safety of botulinum therapy in patients with delayed facial palsy after neurosurgical interventions. MATERIAL AND METHODS: We examined 33 patients with delayed facial palsy developed 3 or more days after resection of vestibular schwannoma. The main group included 18 patients with contraindications to GCSs who received injections of botulinum toxin A (BTA) into the facial muscles of the healthy side for muscle relaxation. The comparison group consisted of 15 patients who received a course of prednisolone (1 mg/kg/day) for 5-7 days. The efficacy of treatment was assessed using the House-Brackmann scale and Clinical Global Impression Scale. The follow-up period after therapy was 3 months. RESULTS: Delayed facial palsy was more common in the following cases: the facial nerve was located near the antero-inferior tumor pole; the tumor was adherent to the facial nerve; the tumor extended in the oral direction; the tumor had with unclear borders and was 11 to 30 mm in size. In most patients of both groups, facial muscle palsy developed more than 11 days after surgery. Treatment both in the main and control groups resulted in a significant improvement: complete regression of the facial asymmetry in patients of the main group and comparison groups 3 months after treatment onset was 83.3 and 93.3% (House-Brackmann scale), respectively. CONCLUSION: Botulinum therapy may be recommended for patients with delayed facial palsy developed after vestibular schwannoma resection, who have contraindications to GCSs.

[Facial nerve injury in neurosurgery: a rehabilitation potential of botulinum therapy]. / Porazhenie litsevogo nerva pri neirokhirurgicheskikh operatsiiakh: reabilitatsionnyi potentsial botulinoterapii.

Surgical treatment of posterior cranial fossa and cerebellopontine angle tumors is associated with a risk of facial nerve dysfunction. The causes for facial muscle paresis include nerve compression by the tumor, destruction of the nerve structure by the tumor growing from nerve fibers, nerve injury during surgical removal of the tumor, etc. The first 3 months after facial nerve injury are a potential therapeutic window for the use of botulinum toxin type A (BTA). During this period, the drug is introduced both in the healthy side to improve the facial symmetry at rest and during mimetic movements and in the affected side to induce drug-induced ptosis. Post-paralytic syndrome develops 4-6 months after facial nerve injury. At this stage, administration of BTA is also an effective procedure; in this case, drug injections are performed on the affected side at small doses and symmetrically on the healthy side at doses doubling those for the affected side. BTA injections are mandatory in complex treatment of facial muscle paralysis.

[Conversion ratio between different botulinum neuroprotein product in neurological practice]. / Sootnoshenie edinits deistviia razlichnykh preparatov botulinicheskogo neiroproteina pri ispol'zovanii v nevrologicheskoi praktike.

Despite nearly 30 years of experience in the application of botulinum toxin type A (BTA) in clinical practice, many fundamental questions of therapy remain valid. There are 5 botulinum toxin type A used for neurological indications in the Russian Federation in 2017. They contain different number of active neuroprotein (150 kDa) in a therapeutic dose of the drug that may have a potential impact on the efficacy and duration of action. The current SmPC of each BTA stated that the unit of activity is unique and can not be compared with any other BTA. In scientific publications one can find many details concerning the equivalence doses of onabotulinumtoxin A (botox) and abobotulinumtoxin A (dysport) and the ratio of units varies from 1:1 to 1:11. However, according to clinical guidelines, systematic reviews and high quality research evidence of recent years, the ratio of units of abobotulinumtoxin A (dysport) and onabotulinumtoxin A (botox) is 3(2,5):1. Use of a fixed ratio of units is possible only when switching from one drug to another or in case of limiting access to specific drug. Botulinum toxin type A is the first line of therapy in the treatment of several neurological diseases. The most commonly used drugs of botulinum toxin type A (botox, dysport, xeomin) have a significant evidence base that confirms their efficacy and optimal safety profile. The main difference between botulinum toxin type A is their potential activity of action, i.e., activity units and total therapeutic dose.

[The efficacy of botulinum toxin therapy in patients with upper limb spasticity due to traumatic brain injury]. / Effektivnost' botulinoterapii v lechenii spastichnosti verkhnei konechnosti u patsientov s cherepno-mozgovoi travmoi.

Spasticity is a type of muscle hyperactivity that occurs in patients after focal lesions of the Central nervous system due to various diseases: stroke, traumatic brain injury or spinal cord injury, neurosurgical intervention, as well as multiple sclerosis and other diseases of the Central nervous system and is the most disability manifestation of the syndrome of upper motor neuron (UMNS). Focal spasticity of the upper limb requires a complex treatment. Botulinum toxin therapy is an effective treatment for focal/multifocal spasticity in reducing muscle tone and improving function with the highest level of evidence according to the latest American and European guidelines for treatment of spasticity. There are many publications devoted to BTA use in post-stroke patients. This article provides a review of the BTA use in patients with the upper limb spasticity due to severe traumatic brain injury. Some local data on the BTA efficacy in the cohort of patients with traumatic brain injury are also presented.

[Electromyographic control of botulinum toxin a injections in the upper extremities in patients with spasticity of various etiology].

AIM: The study was aimed at studying the efficacy of botulinum toxin A injections combined with EMG-control of the injections in patients with upper limb spasticity of various etiology for decreasing muscle tone and improving the passive limb function as well as at assessing the possibility of a botulinum toxin dose reduction under combination of these methods. MATERIAL AND METHODS: 61 patients with upper limb spasticity of different etiology were evaluated. The main group consisted of 29 patients who were injected with abobotulinum, the botulinum toxin A (500 U per vial), under EMG-control. The control group consisted of 32 patients who received BTA injections without EMG-control. A repeated BTA injection was performed on the 4th month of the study. Patients in both groups received standard rehabilitation therapy. The spasticity pattern was determined using the Arm Spasticity Pattern (ASP) scale. Evaluation of the treatment efficacy was performed using the modified Ashworth scale to determine upper limb spasticity and the modified Barthel Index scale to assess the quality of life as well as the Disability Assessment Scale (DAS) and Clinical Global Impression (CGI) scale. RESULTS: The main spasticity patterns were as follows: the type III was in 13 (44.8%) and 17 (53.1%) patients, the type I was in 9 (31.0%) and 9 (28.1%) patients, and the type VI was in 7 (24.2%) and 6 (18.8%) patients of the main and control groups, respectively. One month after BTA treatment, a significant improvement was observed in both groups, but the improvement in the main group was more pronounced compared to that in the control group (р<0.05). This difference persisted for the whole treatment period (р<0.05). The DAS score demonstrated improvement in both groups, but only patients of the main group had a statistically significant improvement in putting the arm through a sleeve (р<0.05). EMG-control enabled a reduction in the BTA dose by 50-300 U. CONCLUSION: BTA injections under EMG-control in upper limb spasticity patients may improve the treatment efficacy.

[The use of botulinum toxin type a in the acute phase of facial nerve injury after neurosurgical surgery].

AIM: To evaluate the role of botulinum toxin type A in the acute phase of facial nerve injury after neurosurgical surgery. MATERIALS AND METHODS: The study involved 55 patients with acute facial muscle paresis caused by facial nerve injury during surgery on the posterior cranial fossa and cerebello-pontine angle (CPA). The first group consisted of 35 patients (mean age, 48.14±1.26 years) who were administered botulinum toxin type A (xeomin) at a dose of 2-3 U per point in muscles of the intact side of the face. The control group included 20 patients (mean age, 49.85±1.4 years) who underwent standard rehabilitation treatment of this pathology. The treatment efficacy was evaluated using the House-Brackmann Scale, the Yanagihara facial grading system, the Facial Disability Index (FDI), and the Sunnybrook Facial Grading (SFG) Scale. RESULTS: Before treatment, patients of both groups experienced severe dysfunction according to the House-Brackmann Scale. A month after the botulinium toxin type A therapy had been started, a significant improvement in the group of patients who received botulinum toxin was observed at all scales (p<0.05), whereas improvement in the facial nerve function in the second group was observed only by the 3rd month of rehabilitation treatment (p<0.05). The number of synkineses in the patients who did not receive botulinum toxin was 46% higher than that in the first group (p=0.019) one year after the surgery, and it was higher by 91% after 2 years (p<0.001). CONCLUSIONS: The use of botulinum toxin type A is reasonable in acute facial nerve injury and should be mandatory in combined therapy of these patients.

[The functional asymmetry of the facial neuromotor apparatus in patients with facial nerve neuropathy and its treatment with botulinum toxin type A lantox].

A clinical and electrophysiological (EMG, ENMG, the blink reflex) examination has been carried out in 85 patients with facial nerve lesions of different etiology. A control group included 25 healthy people. Two schemes of botulinum toxin type A (lantox) injections into hyperactive facial muscles have been elaborated. The second examination has been conducted 14 days after injections. The compensatory tug of paretic muscles accompanied by the hypertonic activity of facial muscles of an intact side has been observed in patients with facial nerve neuropathy. The results of the study have been analyzed in 64 patients stratified into two subgroups: 29 patients with prosopoplegia and 35 patients with late complications. After the treatment, the tone of facial muscles has decreased thus promoting the balance between facial muscles on both sides of the face, decrease in facial asymmetry, increase of the functional muscle interaction between both sides, reduction of pathological synkinetic activity. The authors emphasize that the use of botulinum toxin type A both in the early and recovery stages allows to obtain high functional and esthetic results.

[Vascular decompression in the treatment of trigeminal neuralgia].

Trigeminal neuralgia is characterized by unilateral paroxysmal facial pain. Patients often describe this pain as "the most sever pain one can suffer". Vascular compression of trigeminal nerve root directly near brainstem by artery or vein is considered the main etiology of trigeminal neuralgia. Consequently, basic pathogenetic treatment is vascular decompression of trigeminal nerve root that allows to eliminate the cause of pain. 140 patients with trigeminal neuralgia were operated in Burdenko Neurosurgical Institute since 1998 to 2007. Pain relief after surgery was observed in 96% of cases. There was no mortality in our series, overall delayed complication rate was less than 1,5%. The article deals with clinical presentation of classic trigeminal neuralgia, evaluation of the role of MRI in diagnosis of this disease and description of surgical types of arterial and venous root compression. Authors demonstrated that high effectiveness of vascular decompression depends on correct clinical diagnosis.

[Paradoxical kinesis phenomenon in focal hand dystonia--writer's cramp].

Paradoxical kinesis (PK) phenomenon and its variants, exerting a beneficial influence on dystonia dynamics, are described using self clinical examination of 57 writer's cramp patients. PK was found in all the patients independently of writer's cramp variant, duration and severity. The most frequent writing maneuvers were as follows: hand printed (100%), proximal arm muscles writing (82.5%), individually selected writing instrument (67.5-80%), unusual means (67.5-75%), writing imitation with unlike-pen object (70%), marked papers (52.5%). The beneficial influence of PK phenomenon on dystonia expression may be considered as one of the directions of writer's cramp rehabilitation.

[Clinical and physiological analysis and treatment of writer's cramp]. / Kliniko-fiziologicheskii analiz i lechenie pischego spazma.

Clinical, psychological and electrophysiological features of 43 patients with writer's cramp (WC) were studied. "Complex clinical inventory for patients with a focal dystonia form--writer's cramp" has been elaborated. The stages in the disease development were found and focal and tremor forms were identified. According to electroneuromyography, a tremor form is characterized by higher awkwardness (defect in motor program) and peripheral disability compared to a spastic form. In a spastic form, a movement defect was more local. In WC treatment, complex action on central factors and peripheral mechanisms of pathogenesis is needed. Treatment duration, including clonazepam and motor defect correction, is not less than 12 months. Efficacy of clinical treatment was more pronounced in a spastic form.

[Clinico-physiological analysis of cranial dystonia]. / Kliniko-fiziologicheskii analiz kranial'noi distonii.

To study afferent and efferent mechanisms of both pathogenesis and forming of the symptoms of dystonia a clinical-electrophysiologic examination was performed in 22 aged 35-69 years patients with cranial dystonia. A wide range of different factors in anamnesis of the patients was found, that had had either short or long influence on the facial zone and that had preceded the development of cranial dystonia (2 month-5 years before its rise). This was called by the authors the peripheral factor of dystonia pathogenesis. This peripheral factor may have a starting and maintaining role in pathogenesis of dystonia. The results of electrophysiologic studies (electromyography, method of dermal sympathetic potentials, registration of abdominal reflexes) suggest the presence of diffuse hyperactivity of interneuronal apparatus on different levels of brain stem being, probably, an efferent link in both pathogenesis and symptoms of dystonia as a whole and cranial dystonia, in particular. The conclusion is made that a removal of the peripheral factor as a stable link of pathogenesis of cranial dystonia together with the influence on the efferent link of pathogenesis may be a new aspect in therapy of this disease.