Thank you very much for joining us today. My name is Mohit Bansal. I'm one of the biotech pharma analysts here at Wells Fargo. And this is my first session of the morning, and I'm very happy to have from BioMarin, Greg Fryberg with us. Greg is the EVP and Chief Research and Development Officer at BioMarin. Thank you very much for being here. Yes. Thanks for the opportunity to join you. Great. So I mean, before I get to specific questions, I would love to let you know, it has been how long for you at BioMarin? It's been a year. It has been a year, right? So yes, I mean, I think BioMarin from the science point of view is a great company. I mean, so many rare disease drugs you have developed. So can you talk a little bit about your experience in the last one year? And what investors should look forward to from the R and D engine side of the company. Yes. No, thank you for the opportunity to be here and talk about what I love most, of course, which is the science. I've been at BioMarin for a year now. And of course, when our new CEO joined about eighteen months ago, we began an organizational transformation. A lot of focus on operating margin, but also an attempt to make sure that we're focused on the most high priority programs, opportunity to make the biggest difference for patients and really a focus on genetically defined conditions. We've had a lot of wins over the last couple of months, and we have some activities looking we're looking forward to. In particular, our BMN three thirty three, our long acting CNP program, I'd love to talk about a little bit. We just released some data publicly about a month ago at our earnings call. Similarly, we have three events coming up: one, filing for adolescent expansion for our Palynziq project for PKU. We are turning over a card with our newest member of the stable of assets, BMN401. This is the Enzyme program, a first in class first in disease therapy for ENPP1 deficiency. We'll turn over a card for the so called ENERGY three study in the first half of next year. And finally, for Voxogo, the hypochondroplasia program, which recruited about five months ahead of schedule, we saw that as a very good sign. We'll be turning over the card for that pivotal study next year in the late second half as well. So more to come there. And again, it's not just about internal innovation. Part of our evolution, James Sabri joined our organization just one week after I joined. And we're thinking about R and D not simply as sourced internally, but really internal and external innovation are going to be part of our future. We'll judge external science just like we judge our internal science, make tough calls when we need to. But business development is a large part of our activities right now. The Innosyme transaction was the first of what we hope will be many, not only in the early space, but also looking at some late stage assets. So more to come there, but it's busy times. And it's good, of course, we now based on some of the transformation we've been going through, we've got cash and we've got free cash flow. So it's a good time to go out and try to find additional innovation to bring into the stable. Great. Thank you very much for this overview. One question I want to ask is that in the last eighteen months, the company has gone through a lot of rationalization of R and D in terms of what makes sense, what doesn't make sense. And you were part of some of those processes, and some were in place before you joined as well. So can you walk us through, like, what when you look at prioritizing an asset and deprioritizing, what do you really do? Well, that's the magic that we do in R and D. We try to pick winners. But it's humbling. You have to be you look at the science, but also look at what the needs of the world are. Right. And the realities of where a medicine you'll be bringing forward will plug into that world. So we apply not only rigorous scientific standards to our programs, but we also develop target product profiles. We do market research. And we make sure at very early stages that that cross functional dialogue is happening and that the molecules we're bringing forward have a chance to be embraced by society. I would say that there's no one size fits all. You can only know so much about what the world is going look like in the next ten years. But when we go through that process, when we apply those rigorous filters, mean, I there's some examples in the last eighteen months where we've deprioritized and terminated programs. Partially, a few of them we just thought were not good bets. They weren't going to deliver what patients wanted and needed. Others, regulatory endpoints, or the time that it would take to get from here to there were just going to be too long. And we have a fixed, of course, R and D budget. It grows every year. But we want to make sure we're spending those research dollars, the time and effort, and the patient time on molecules that we think will bring the most value. The only truism I would say that we hold really steady to and don't waver from is that we are a company that focuses on genetically defined conditions. We develop medicines for them, but we also help shape the way that those diseases are defined and the way medicine is practiced. And so we're continuing in that space. But beyond that, again, lots of opportunities both internally and in the business development realm. Got it. So I mean, on that, I mean, something that can really be helpful for the patients. I mean, March, the recent data you generated, it was in healthy volunteers, but at the same time, can you talk a little bit about the significance of that? Also, like, I mean, you have Voxsogo, but then there is a longer acting CNP competition coming. In the context of how the field could be in four to five years, what is the significance of these data? So if I could take Voxoggo first, if that's Okay. Voxoggo is a safe and effective therapy for achondroplasia. I mentioned we're hoping that the related but distinct condition of hypochondroplasia will be turning a card over soon. And we're continuing to develop data both in those settings as well as in new indications. What I would say with Voxogo is we see it as our duty to leverage the six thousand plus patient years of experience in now 52 countries around the globe and growing to make sure that we communicate and patients understand the value of the therapy. This isn't a drug that's simply meant to stimulate growth. We talk about growth a lot, we talk about annualized growth velocity, but that's not what the patients care about. They care about their health and their wellness. And that means we need to do a better job, and we will continue to do so, analyzing, developing, publishing our data with regard to those angles of health and wellness. This is tibial bowing. This is spinal stenosis. This is looking at angles of the spine, looking at facial morphology, looking of course at quality of life, all of the health and wellness factors that we're familiar with that unfortunately achondroplasia patients can suffer from. We're going to continue to develop that data. We're going to develop the molecule further as well. We're developing a citrate free formulation and we're going to continue to spread around the globe. We see again tremendous unmet need in other countries and we're going to continue to find those patients. But we're not going to stop there. We're thinking about this molecule as the beginning of a franchise, a CNP franchise. Now we pioneered the biology here. CNP 39 is, you know, the 39 amino acids are something we're quite proud of that elongate the half life beyond what natural CNP, which has a half life only of a few minutes can provide. Now by not stopping there, we've also generated a long acting molecule in BMN three thirty three that uses an albumin binding peptide and essentially creates almost like a molecular depot effect where low levels of CNP will be released into the bloodstream. What that accomplishes is you avoid the very high Cmaxs, where we can see excursions in heart rate and blood pressure that we want to be avoided. They're not life threatening, but they certainly are to be avoided. And it also allows us to increase the AUC exposure of CNP to levels that in animal models are giving us continuing increases in growth when we increase AUCs beyond what's seen with Voxogo and beyond what's seen with other long acting CNP agents. What we predict from the mouse models is that an AUC of roughly threefold or higher can unlock growth on the order of twice as much attributable growth as compared to the comparator arms. Will we see that in humans? To be determined. But what we have in March, the new data that we've discussed, is we have the right reagent to test this hypothesis. The animal models suggest that there's more growth to be had. There's genetic data from human systems. There are very rare individuals with high CNP levels or activations of NPRB pathways that grow to be seven feet tall or more without non scalable side effects also. So it appears like other than at the bone, these are going to be areas that could be quite safe. And then, of course, looking at other long acting CNP agents that are on the market, there does appear to be a dose response relationship as you march up the curve. The question that hasn't been tested, the final question, is does that curve keep going in humans when you have higher AUCs? We believe that that's a good bet, and we now know that we have a molecule that in multiple cohorts we've seen AUCs above 3x. It's a six cohort study. We mentioned in both cohort four and five, we had met that criteria for moving forward. And six, of course, just completed. So in that regard, starting a combined phase twothree program in the first half of next year off to the races in achondroplasia. The hope is to have a superior growth profile. It will be there'll be a comparative effectiveness study directly against Loxogo as the Phase III portion. And we hope to have that program available with data to be on the market by the 2030 time frame. Got it. We're going through a lot of exercises to try to speed that up, but we're committed to the 2030 time frame as we speak with the goal of beating that as well. Got it. Now so let's just I want to talk a little bit about this AUC aspect of it. So do we know so when you say 3x of AUC, it is compared to the long acting CNP, not with VOXSOGO, right? So it's compared to both simulated long acting as well as a VoxoGo. Got it. When we lock those into the animal models, we see in a linear fashion. As we go up on AUC, there's more growth to be had. The 3x just happens to be a threshold where we saw significant Got it. So did you see higher AUC for the longer acting CNP, the comparator CNP versus Voxsogo? When you well, so the short answer is yes. But if you take the AUC of the spike shaped profile of Voxsogo and you multiply it times seven doses, the AUCs are actually in a similar ballpark. Got it. I don't know if that's really a useful math exercise. The concept of Voxsogo, of course, is that there's pulsatile activation of the pathway, kind of like running the first 100 meters of a mile race and then maybe walking the rest of it. Whereas long acting is more of a smooth jog over the course of the whole mile. The biology, at least looking at the published data for long acting versus Voxsogo, it looks quite similar in terms of growth data. The data are too, right? Yeah. And so I think that that gives us confidence that we're not going to see, say, like with parathyroid hormone, dramatically different biology from pulsatile versus continuous. Though I suppose with long acting, again, longer follow-up, all we have is one year data, longer follow-up, and additional time points are needed. Clearly, with 03/30 three, we believe that that's a good bet. And we believe that there's going to be so called more meat on the bone here. There's an opportunity to continue to go higher, and we hope that that benefits patients. We talk a lot about growth. We talk about it in the animal models. It's what we can measure. But the implication is that we're pulling through to those measures of health and wellness as well. Got it. So this is the other question is that these patients have, at least the trial, you enrolled about four centimeters of growth velocity per year on the baseline. The baseline, and these drugs can actually get to one and a half centimeters extra per year. How much more you can extract out of this mechanism? Could it be like two, two and a half centimeters? Like what is the normal, six, six and a Well, so when I talk to pediatric endocrinologists, they remind me that teenage boys in their growth spurt can reach 10 or even 12 So centimeters a again, physiologically, there are opportunities there. But what we're looking for is to improve upon Voxsogo. We know Voxsogo roughly, a 14 year old boy with achondroplasia probably has an 18 inches growth deficit compared to normal stature peers. If you extrapolate out over the course of their entire life, Oksogo probably can achieve, you know, about ten ten centimeters I'm sorry, 10 inches of growth of that 18. Clearly, we'd like to do better. We'd like to be able to restore to average stature. So there is additional growth to be had. The challenge, of course, is that not all growth is linear in these patients. There are two particular growth sinks, so to speak. One is at the time of birth. These patients are achondroplasia patients are already growth deficient and they don't have a typical growth spurt also in the teenage years. So to make up for that, we know something north of the 1.5 centimeters is needed. It's hard to know where the top is. But clearly, something between 1.5 and the growth curves of a normal stature individual, that's what we're looking for. Got it. And I want to bring in the the the question about the growth hormones as well. Yeah. So, I mean, I think competitors shared some data in combination with growth hormones. Yeah. There's like, there's this thought process that, you know, growth hormones, where they were, they actually give you a nice growth initially, right? And then, and that's, like, you can see the difference by and all of me, because of the mechanism, it's like over a slope of time. Do you see a reason to use a CNP in combination with growth hormones? Yeah, it's a tricky question. If I ask the question slightly differently, why does the world not use growth hormone in achondroplasia with the exception of Japan? And the answer has historically been that growth hormone is great in growth hormone deficient condition. This is not a growth hormone deficient condition. Growth hormone is also not a targeted therapy. There's a variety of downstream effects. And in achondroplasia patients, historically, you can uncork additional growth, but it doesn't tend to last. Over the course of one to two years in achondroplasia, you tend to see a waning effect in terms of growth velocity increases. When you look at final adult height, you know, a variety of publications, you also don't see a dramatic difference with growth hormone in achondroplasia. So hypothetically, the concern here is that you're accelerating bone growth, but it's at the expense of bone age and perhaps closing the growth plates earlier. These are, I think, the concerns that will only be alleviated by looking at longer endpoints. Six months is not going to be enough time to see, is this a persistent increase? Are there accelerations of bone age? So additional time is absolutely going to be needed. What I believe that these patients need and what the future will ultimately bring forward are more rational combinations thank you so much where, again, as we develop the data, I think we'll get a better idea of phenotypes and genotypes of patients that responding more favorably or less favorably, whether it's the CNP or FGFR3, and thinking about a future with rational targeted combinations, rational targeted sequences, I don't believe growth hormone is going to necessarily be the major player there, though again, more to be seen, and we'll have to see. Growth hormone also comes with other side effects and challenges. The pediatric endocrinologists are well aware and can handle the intracranial pressure increases. But soft tissue hyperplasia. There are a variety of cardiovascular effects. Again, we're talking about children, children who are going to be on these therapies for years at a time during their formative years. These drugs can be used. But we should ask the longer term safety question when we think about adding a second drug like growth hormone. Makes sense, actually. Thanks for the water. Of course. So let's just talk a little bit about the plans for registration study. I mean, you are planning to start it in next next year. For March? For March. You are talking about there could be a superior profile to Roxulgo, but again, I'm That's the ambition. That's the ambition. So how do you design a trial like that? And and do you go for CNP naive patients? You go for experienced patients? Because, I mean, by that time, there will be a lot of patients already on CNP, right? So like I say, it reminds me of Alexion, right, back in the days when they were trying to develop Alzheimer's. One hundred percent. Right? So how do you think about this? First and foremost, we think asking patients to sign up to a placebo controlled study is a tall order. So we've designed a study that has no placebo arm. We've been able to model the data that we have. We also want to make sure whatever our control arm is that we buttress it. We supplement it. We borrow statistically as much data as we can from Save Oxogo. And we've been working with regulators again to design that study. The study we're envisioning, it's not locked in yet. Again, a study concept, of course, has been reviewed with a variety of regulators around the globe. The study we're envisioning is a combination Phase IIIII study. The Phase II portion, which will begin in the first half of next year, We'll look at up to three doses of BMN three thirty three, call it high, medium, and low to be determined. And there'll be a fourth arm, which will be a Voxogo control arm. We will run that in achondroplasia patients, look at six month AGV, and again then pick the winner moving forward and ultimately do a bake off, a straight up comparative effectiveness study of the chosen dose of three thirty three against VOXZOGO. That study would be powered to again to look for superiority. We believe, again, that's what the marketplace wants. That's what patients want. That's what they demand. We're envisioning, again, weekly dosing at this point. And that is really to optimize the AUC profile. Theoretically, you could spread out the doses more, but that's not what we're highlighting right now. And through this study, again, we're hoping to have a registration package that would be available for approval in 02/1930. And of course, we're pulling all the levers that we can to move that as quickly as possible. Right now, we're committed to 02/1930. And regulatory landscape seems to have changed as well around one year now, right? I mean, so people FDA is probably looking for one year at this point rather than two years, or I believe the FDA has a bit of regulatory flexibility flexibility here. Here. With regard to the pivotal study, it appears that one year is now acceptable for a filing package if you have supportive data from other studies from other areas of longer term efficacy. Got it. There also are always opportunities and post marketing commitments that could be put in. But yes, one year appears to be a reasonable endpoint at which we could engage the agency after a Phase III study. Got it. And non placebo controlled trial will probably help with the enrollment speed and at the same time? Yeah, we're really hoping. And from that standpoint, it will be important for us to pick the sites and the countries appropriately. Of course, again, a switching study would be planned as part of the overall package, pediatric plan, a hypochondroplasia plan to be determined. It all begins, though, with this dose ranging in achondroplasia. I just want to take a step back. We're moving from single dose healthy volunteer and jumping directly into multi dose patient phase two. That's been agreed upon, and I think it reflects again the comfort level that physicians, patients, regulators have with the CNP pathway. They understand the biology here and feel comfortable moving into patients at this point. Great. So how about we talk a little bit about, like, moving away from $3.33 now, and then talk about the other new asset, the DMD asset, So so at this I think you are planning to share some data by end of this year. So can you talk a little bit about what to expect there, what data will this is we call it BMN351. It's an antisense oligonucleotide. It's targeting exon 51 skip amenable to Shane's muscular dystrophy patient. So it's not a gene therapy. Again, very sad, the news with the AAV therapies. This fortunately can avoid that, though ASOs have their own safety challenge. When you dose up a high enough mass of antisense oligonucleotides, inevitably, whether it's kidney tox, liver tox, or platelet toxicity, those are expected to be seen, and I would call them even class effects. Now inherent in what I just said though is that the goal for Duchenne's muscular dystrophy is to find that therapeutic window. Put in enough skip product, generate enough surgically altered mRNA product that produces near full length dystrophin, not microdystrophin, but near full length dystrophin. That's the goal of the therapy. And we've designed a molecule. It's a non morpholinochemistry for those who are organic chemistry aficionados. But it also targets a skip induction site that we think will be a much more potent producer of the skip product. So the strategy here is not that we have a biodistribution engine to the muscle per se, but that the drug that gets there will be able to do its job better and produce more product. One of the downsides of that is that takes a lot of time. The tissue half life of this program is such that we don't expect to reach steady state dystrophin levels till out at a year or more. So we're not going to sit around and wait for that. We're running a study in patients with Duchenne's. They are treated at one of three dose levels, six milligrams per kilogram, nine milligrams per kilogram, or twelve milligrams per kilogram. It's weekly dosing. And we were pleased that, again, the twelve milligram per kilogram opened recently. The DMC allowed us to do that. But the six and the nine have completed dosing, and we're waiting to get all the biopsy data results back. We are looking for a fairly ambitious dystrophin level. We are looking for a 10% non adjusted dystrophin level in the muscle of patients. Now what does that mean? Well, means actually at the six month time point, you'll probably be in the three percent to 5% range. But you'll be on the way up the curve to the ten percent. That's what success would look like to us. And the question becomes, is that achievable with these programs? We will have that data in those first two cohorts by year's end, and we'll make some sort of announcement release of that data. We'll also certainly have combined safety data in the products. And we will have a first look, though this endpoint takes even longer than dystrophin. We'll have a first look at our stride velocity 95C data. I would say that the data produced by Dine is probably the best benchmark for what good looks like in this space right now. That 10% target that we have would be equivalent to a 3.2% with Dyne. Their 8% number is fat muscle adjusted. We're not using that as we talk about the math. So we'd be looking for dystrophin levels that are superior to what Dyne's shown. And again, the Stride Velocity 95C data that they've seen, which is quite encouraging. We'd hope to be able to see something superior to that as well. The question, course, will be whether or not we can achieve that. And that's what we'll be turning the cards over and getting a first look at. This is a weekly therapy. So we want to make sure that if we're asking patients to undergo that sort of therapy, that we have the right efficacy and safety profile. But more to come, but we're right at the precipice of being able to turn some cards over. Awesome. So this will be six month data. The goal is to get to expect ten percent here. Correct. Three to six percent is what you are looking for? Yep. And Diana showed three point three percent at the same time frame, roughly. A little bit. Yeah. Roughly the same time frame, but with a much shorter half life, much shorter tissue half life. And also a muscle distribution engine that just the pharmacokinetics will look different. Got it. I'll, you know, again, say the DINE data is great for patients. Great to see the breakthrough designation as well suggests that the FDA agrees that those sort of levels are meaningful for patients. Those sort of functional data are meaningful for patients. Our goal is to have a product that, again, will have some superior profile. Got it. And for stride velocity, we should not expect anything at six months in terms of I don't think we can expect anything at six months. It usually is an endpoint that would pull through and take several quarters after you reach steady state. But we will be measuring it. And we want to, again, tip my hat to some of the pioneering work that's been done by others. That appears to be a quantifiable, reproducible, and a good measure of how these children are doing with regard to their functional aspects, their mobility. Better than six minute walk as well? Better than six minute walk. Got it. Yeah. Yeah. Much well, it's like an Apple Watch for your ankle. And so you can imagine it's sampling through the whole day. If you take the slice of the quickest velocity of 5%, it's going to be similar to twenty four hour blood pressure monitoring, better than spot checks. Got it. So can you help remind us what did etaplisense show at that time from So we picked the 10%. Let's see if this is what you were asking. Because we've looked at genetic databases and seen that if one has a 10 level or higher, their phenotype behaves much more like a Becker's muscular dystrophy, where ambulation is and we can look at this with codes and Medicare and UK database system. Ambulation is maintained into the 30s and 40s, and the patients live into their 50s and 60s. That's very different than Duchenne's where ambulation sadly, you know, in their early teen years is the loss of ambulation would be the norm. And of course, succumbing to their illness in their 20s and 30s, devastatingly different. The hope is, again, near full length dystrophin at this ten percent level, we would hope that that would unlock a very meaningful change in the course of disease. We'd have to prove that. But again, it starts by having a reagent that can deliver that kind of a profile. Got it. Very helpful. And then what about the safety side of it, right? I mean, it should have the ASO level safety, or is there Yeah, we do expect that there will be class effects on the ASOs. This is phosphothioate chemistry. Again, a prior molecule was able to, at the six milligram per kilogram level, have a profile that had no irreversible renal toxicity. We, of course, have studied nine and now twelve milligrams per kilogram. The data monitoring board has looked at a whole variety of kidney toxicity measures and has agreed to move forward and allowed us to go to twelve milligrams per kilogram. We see that as a good sign. But we are watching very carefully, both the liver and the kidney, for potential toxicity. We expect that ASOs at some level will reach these. And so the question, as with gene therapies, as with other ASOs, will be can you thread that needle? We're hoping that the PK profile that we have, this loading up of the tissue, long tissue half life, will again allow us to open up that window. We don't have to give big boluses once a month. We're giving weekly doses in order to be able to open that window. Got it. That's very helpful. Maybe last few minutes. So quickly, if I want to talk about, how should we think about the hypochondroplasia data when they come out? What is the bar for success? Hypochondroplasia is a short stature disorder, short stature condition that actually is a mutation in the same receptor as achondroplasia. It's different mutations. It has a slightly different pull through of phenotype. Children are often diagnosed later, more like five or six years old, rather than achondroplasia where it's often in utero diagnosis. But there is a misconception that hypochondroplasia is just mild achondroplasia. It's not actually true. Number one, we've refined for a population that are more severely affected. Most of the patients will be minus three standard deviations in height or less. That means more negative. And we've done some epidemiology work. Hypochondroplasia patients actually are five times as likely to have orthopedic complications in their life. They're four times ENT. And sadly, they have an increased risk of mortality over their lifetime, increased hospitalization, health care utilization. Building the evidence around that urgency to treat hypochondroplasia will be part of our story here. What we can expect out of Voxogo, I think there's two sources of reassurance that we're going to see a safe and effective drug for this indication. Number one, Doctor. Dauber, one of our collaborators, has run an investigator sponsored study and again saw that not only does Voxelgo work in these patients, but probably to a greater degree than what we see with achondroplasia, the hypothesis being that the less dysplastic of the growth plate, so the more orderly progression of the chondrocytes, the more responsiveness there may be to CMP. That's one data set. And then again, I would say that just from medical standpoint, and of course, with the receptors being the same, there is a belief that these indications will behave quite similarly. Got it. And that's why we didn't have to do another dose ranging phase two. We could jump right to phase three, even though all we had was achondroplasia data before we started that study. The study recruited about five months faster than we had anticipated, again speaking, we think, to the unmet need and the desire to have a therapy. And the study is powered to look for a size, a growth velocity acceleration similar to Voxsogo. We're hoping it will be larger than that. Doctor. Dauber's data would suggest that it will be larger than that. But the conservative assumption is that it can measure a difference similar to achondroplasia. Awesome. So similar topic for BMN four zero one. Like, we'll have data for top line next year. So I mean, what should we expect there? So ENPP1 deficiency is rare, and it's devastating, particularly in infants. There are three phenotypes of the disease. There are the infants, where, again, only about half of them even live outside their forty percent to fifty percent can live beyond the first year strokes, really terrible burden of illness there. There are children where rickets, soft bones, hearing loss tend to be the major phenotypic pain challenges. And then there are adults who have more osteomalacia, again, soft bones, pain, calcification in joints. Because when this enzyme is missing, there's a double whammy of effects. Not only do bones get soft, but paradoxically the calcium goes where you don't want it to go. It goes to arteries. It goes to other tissue beds. And so this is a product. It's an ENPP1 enzyme replacement. It's an Fc fusion, so it can be manufactured pretty easily. Great work by the Enazyme team to get us here and show us that across a broad variety of indications, all those age groups, you can increase these biochemical markers. Pyrophosphate normalizes in days to a couple of weeks. And the pull through to functional endpoints is what the ENERGY three study will be studying in children. This is the one to 12 year old. We'll be turning over that card in the first half of next year. And that will be the beginning. We are going to run an adult study as well. We're working on the phase three protocol right now. We have infant data that we'll be certainly showing to regulators and getting their opinion on at any engagement that moves on. The first shot on goal is ENERGY three. We may have the opportunity to extend that study if additional time or additional dosing work is needed. Bottom line is, though, we feel very confident that we can normalize pyrophosphate across all these different groups, including some we didn't talk about, like calyphylaxis and ABCC6 deficiency. There'll be more to come here. We closed the deal on July 1, and I'll just tell you that the integration is going well. Thrilled to have this molecule. We think it will be an important part of our stable moving forward. And really, it's a BioMarin drug. It fits with what we do right on top of our enzyme therapies. And again, we see real value for patients and for stockholders and for BioMarin. Awesome. On that high note, thank you very much for joining us. You have a lot going on.